Arthropodicidal anthranilamides

ABSTRACT

This invention provides compounds of Formula 1, their N-oxides and agriculturally suitable salts  
                 
 
     wherein  
     R 1 , R 2 , R 3 , R 4a , R 4b  and R 5  are as defined in the disclosure.  
     Also disclosed are methods for controlling invertebrate pests comprising contacting the invertebrate pests or their environment with a biologically effective amount of a compound of Formula 1 or a composition comprising a compound of Formula 1.

BACKGROUND OF THE INVENTION

[0001] This invention relates to certain anthranilamides, theirN-oxides, agriculturally suitable salts and compositions, and methods oftheir use for control of invertebrate pests such as arthropods in bothagronomic and nonagronomic environments.

[0002] The control of invertebrate pests such as arthropods is extremelyimportant in achieving high crop efficiency. Damage by invertebratepests to growing and stored agronomic crops can cause significantreduction in productivity and thereby result in increased costs to theconsumer. The control of invertebrate pests in forestry, greenhousecrops, ornamentals, nursery crops, stored food and fiber products,livestock, household, and public and animal health is also important.Many products are commercially available for these purposes, but theneed continues for new compounds which are more effective, less costly,less toxic, environmentally safer or have different modes of action.

[0003] NL 9202078 discloses N-acyl anthranilic acid derivatives ofFormula i as insecticides

[0004] wherein, inter alia,

[0005] X is a direct bond;

[0006] Y is H or C₁-C₆ alkyl;

[0007] Z is NH₂, NH(C₁-C₃ alkyl) or N(C₁-C₃ alkyl)₂; and

[0008] R¹ through R⁹ are independently H, halogen, C₁-C₆ alkyl, phenyl,hydroxy, C₁-C₆ alkoxy or C₁-C₇ acyloxy.

SUMMARY OF THE INVENTION

[0009] This invention pertains to a compound of Formula 1, its N-oxideor an agriculturally suitable salt of the compound

[0010] wherein

[0011] R¹ is CH₃, F, Cl or Br;

[0012] R² is F, Cl, Br, I or CF₃;

[0013] R³ is CF₃, Cl, Br or OCH₂CF₃;

[0014] R^(4a) is C₁-C₄ alkyl;

[0015] R^(4b) is H or CH₃; and

[0016] R⁵ is Cl or Br.

[0017] This invention also pertains to a composition for controlling aninvertebrate pest comprising a biologically effective amount of acompound of Formula 1 and at least one additional component selectedfrom the group consisting of surfactants, solid diluents and liquiddiluents. This invention also pertains to a composition comprising abiologically effective amount of a compound of Formula 1 and aneffective amount of at least one additional biologically active compoundor agent.

[0018] This invention also pertains to a method for controlling aninvertebrate pest comprising contacting the invertebrate pest or itsenvironment with a biologically effective amount of a compound ofFormula 1 (e.g., as a composition described herein). This invention alsorelates to such method wherein the invertebrate pest or its environmentis contacted with a biologically effective amount of a compound ofFormula 1 or a composition comprising a compound of Formula 1 and abiologically effective amount of at least one additional compound oragent for controlling invertebrate pests.

[0019] This invention further relates to a benzoxazinone compound ofFormula 2

[0020] wherein

[0021] R¹ is CH₃, F, Cl or Br;

[0022] R² is F, Cl, Br, I or CF₃;

[0023] R³ is CF₃, Cl, Br or OCH₂CF₃; and

[0024] R⁵ is Cl or Br;

[0025] which is useful as a synthetic intermediate for preparing acompound of Formula 1.

[0026] This invention also relates to a pyrazolecarboxylic acid compoundof Formula 4

[0027] wherein

[0028] R³ is CF₃, Cl, Br or OCH₂CF₃; and

[0029] R⁵ is Cl or Br;

[0030] which is useful as a synthetic intermediate for preparing acompound of Formula 1.

DETAILS OF THE INVENTION

[0031] In the above recitations, the term “alkyl”, used either alone orin compound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl isomers. One skilled in the art willappreciate that not all nitrogen containing heterocycles can formN-oxides since the nitrogen requires an available lone pair foroxidation to the oxide; one skilled in the art will recognize thosenitrogen containing heterocycles which can form N-oxides. One skilled inthe art will also recognize that tertiary amines can form N-oxides.Synthetic methods for the preparation of N-oxides of heterocycles andtertiary amines are very well known by one skilled in the art includingthe oxidation of heterocycles and tertiary amines with peroxy acids suchas peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide,alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate,and dioxiranes such as dimethydioxirane. These methods for thepreparation of N-oxides have been extensively described and reviewed inthe literature, see for example: T. L. Gilchrist in ComprehensiveOrganic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press;M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol.3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R.Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol.43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B.Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A.R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H.Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry,vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., AcademicPress.

[0032] Compounds of this invention can exist as one or morestereoisomers. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. One skilled in theart will appreciate that one stereoisomer may be more active and/or mayexhibit beneficial effects when enriched relative to the otherstereoisomer(s) or when separated from the other stereoisomer(s).Additionally, the skilled artisan knows how to separate, enrich, and/orto selectively prepare said stereoisomers. Accordingly, the presentinvention comprises compounds selected from Formula 1, N-oxides andagriculturally suitable salts thereof. The compounds of the inventionmay be present as a mixture of stereoisomers, individual stereoisomers,or as an optically active form.

[0033] The salts of the compounds of the invention include acid-additionsalts with inorganic or organic acids such as hydrobromic, hydrochloric,nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic,malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic orvaleric acids.

[0034] Preferred compounds for reasons of cost, ease of synthesis and/orbiological efficacy are:

[0035] Preferred 1 Compounds of Formula 1 wherein R^(4a) is C₁-C₄ alkyland R^(4b) is H; or R^(4a) is CH₃ and R^(4b) is CH₃.

[0036] Preferred 2 Compounds of Preferred 1 wherein R⁵ is Cl.

[0037] Preferred 3 Compounds of Preferred 2 wherein R^(4a) is CH₃,CH₂CH₃, CH(CH₃)₂ or C(CH₃)₃.

[0038] Preferred 4 Compounds of Preferred 3 wherein R² is Cl or Br.

[0039] Preferred 5 Compounds of Preferred 4 wherein R¹ is CH₃.

[0040] Preferred 6 Compounds of Preferred 4 wherein R¹ is Cl.

[0041] Preferred 7 Compounds of Formula 1 wherein R¹ is CH₃, Cl or Br,R² is F, Cl, Br, I or CF₃; R³ is CF₃, Cl or Br; R^(4a) is C₁-C₄ alkyl;R^(4b) is H; and R⁵ is Cl or Br.

[0042] Specifically preferred is a compound of Formula 1 selected fromthe group consisting of:

[0043] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is CF₃,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0044] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is CF₃,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0045] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Br,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0046] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Br,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0047] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Cl,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0048] the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Cl,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0049] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is CF₃,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0050] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is CF₃,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0051] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Br,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0052] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Br,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0053] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Cl,R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0054] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Cl,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0055] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ isOCH₂CF₃, R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;

[0056] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ isOCH₂CF₃, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;

[0057] the compound of Formula 1 wherein R¹ is Cl, R² is Cl, R³ is Br,R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl; and

[0058] the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ isOCH₂CF₃, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl.

[0059] The preferred compositions of the present invention are thosewhich comprise the above preferred compounds. The preferred methods ofuse are those involving the above preferred compounds.

[0060] Of note are compounds of Formulae 1, 2 and 4 wherein R¹ is CH₃,Cl or Br; R² is F, Cl, Br, I or CF₃; R³ is CF₃, Cl or Br; R^(4a) isC₁-C₄ alkyl; R^(4b) is H; and R⁵ is Cl or Br.

[0061] The compounds of Formula 1 can be prepared by one or more of thefollowing methods and variations as described in Schemes 1-11. Thedefinitions of R¹, R², R³, R^(4a), R^(4b) and R⁵ in tie compounds ofFormulae 1-24 below are as defined above in the Summary of the Inventionunless indicated otherwise.

[0062] Compounds of Formula 1 can be prepared by the reaction ofbenzoxazinones of Formula 2 with C₁-C₄ alkyl amines as outlined inScheme 1.

[0063] The reaction can be run neat or in a variety of suitable solventsincluding tetrahydrofuran, diethyl ether, dichloromethane or chloroformwith optimum temperatures ranging from room temperature to the refluxtemperature of the solvent. The general reaction of benzoxazinones withamines to produce anthranilamides is well documented in the chemicalliterature. For a review of benzoxazinone chemistry see Jakobsen et al.,Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and referencescited within. See also G. M. Coppola, J. Heterocyclic Chemistry 1999,36, 563-588.

[0064] Benzoxazinones of Formula 2 can be prepared by a variety ofmethods. Two methods that are especially useful are detailed in Schemes2-3. In Scheme 2, a benzoxazinone of Formula 2 is prepared directly viacoupling of a pyrazolecarboxylic acid of Formula 4 with an anthranilicacid of Formula 3.

[0065] This involves sequential addition of methanesulfonyl chloride inthe presence of a tertiary amine such as triethylamine or pyridine to apyrazolecarboxylic acid of Formula 4, followed by the addition of ananthranilic acid of Formula 3, followed by a second addition of tertiaryamine and methanesulfonyl chloride. This method generally affords goodyields of the benzoxazinone and is illustrated with greater detail inExample 1.

[0066] Scheme 3 depicts an alternate preparation for benzoxazinones ofFormula 2 involving coupling of a pyrazole acid chloride of Formula 6with an isatoic anhydride of Formula 5 to provide the Formula 2benzoxazinone directly.

[0067] Solvents such as pyridine or pyridine/acetonitrile are suitablefor this reaction. The acid chlorides of Formula 6 are available fromthe corresponding acids of Formula 4 by known methods such aschlorination with thionyl chloride or oxalyl chloride.

[0068] Anthranilic acids of Formula 3 are available by a variety ofknown methods. Many of these compounds are known. As shown in Scheme 4,anthranilic acids containing an R² substituent of chloro, bromo or iodocan be prepared by direct halogenation of an unsubstituted anthranilicacid of Formula 7 with N-chlorosuccinimide (NCS), N-bromosuccinimide(NBS) or N-iodosuccinimide (NIS) respectively in solvents such asN,N-dimethylformamide (DMF) to produce the corresponding substitutedacid of Formula 3.

[0069] Preparation of the isatoic anhydrides of Formula 5 can beachieved from isatins of Formula 9 as outlined in Scheme 5.

[0070] Isatins of Formula 9 are available from aniline derivatives ofFormula 8 following literature procedures such as F. D. Popp, Adv.Heterocycl. Chem. 1975, 18, 1-58 and J. F. M. Da Silva et al., Journalof the Brazilian Chemical Society 2001, 12(3), 273-324. Oxidation ofisatin 9 with hydrogen peroxide generally affords good yields of thecorresponding isatoic anhydride 5 (G. Reissenweber and D. Mangold,Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223). Isatoic anhydrides arealso available from the anthranilic acids 3 via many known proceduresinvolving reaction of 3 with phosgene or a phosgene equivalent.

[0071] Pyrazolecarboxylic acids of Formula 4 can be prepared by themethod outlined in Scheme 6.

[0072] Reaction of pyrazole 10 with a 2,3-dihalopyridine of Formula 11affords good yields of the 1-pyridylpyrazole 12 with good specificityfor the desired regiochemistry. Metallation of 12 with lithiumdiisopropylamide (LDA) followed by quenching of the lithium salt withcarbon dioxide affords the pyrazolecarboxylic acid of Formula 4.Additional procedural details for this method are provided in Examples1, 3 and 5.

[0073] The starting pyrazoles 10 wherein R³ is CF₃, Cl or Br are knowncompounds. Pyrazole 10 wherein R³ is CF₃ is commercially available.Pyrazoles 10 wherein R³ is Cl or Br can be prepared by literatureprocedures (H. Reimlinger and A. Van Overstraeten, Chem. Ber. 1966,99(10), 3350-7). A useful alternative method for the preparation of 10wherein R³ is Cl or Br is depicted in Scheme 7.

[0074] Metallation of the sulfamoyl pyrazole 13 with n-butyllithiumfollowed by direct halogenation of the anion with eitherhexachloroethane (for R³ being Cl) or 1,2-dibromo-tetrachloroethane (forR³ being Br) affords the halogenated derivatives 14. Removal of thesulfamoyl group with trifluoroacetic acid (TFA) at room temperatureproceeds cleanly and in good yield to afford the pyrazoles 10 wherein R³is Cl or Br respectively. Further experimental details for this methodare described in Examples 3 and 5.

[0075] As an alternative to the method illustrated in Scheme 6,pyrazolecarboxylic acids of Formula 4 wherein R³ is CF₃ can also beprepared by the method outlined in Scheme 8.

[0076] Reaction of a compound of Formula 15 wherein R⁶ is C₁-C₄ alkylwith a suitable base in a suitable organic solvent affords the cyclizedproduct of Formula 16 after neutralization with an acid such as aceticacid. The suitable base can be, for example but not limitation, sodiumhydride, potassium t-butoxide, dimsyl sodium (CH₃S(O)CH₂ ^(⊖) Na^(⊕)),alkali metal (such as lithium, sodium or potassium) carbonates orhydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammoniumfluorides or hydroxides, or2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphonine.The suitable organic solvent can be, for example but not limitation,acetone, acetonitrile, tetrahydrofuran, dichloromethane,dimethylsulfoxide, or N,N-dimethylformamide. The cyclization reaction isusually conducted in a temperature range from about 0 to 120° C. Theeffects of solvent, base, temperature and addition time are allinterdependent, and choice of reaction conditions is important tominimize the formation of byproducts. A preferred base istetrabutylammonium fluoride.

[0077] Dehydration of the compound of Formula 16 to give the compound ofFormula 17, followed by converting the carboxylic ester function tocarboxylic acid, affords the compound of Formula 4. The dehydration iseffected by treatment with a catalytic amount of a suitable acid. Thiscatalytic acid can be, for example but not limitation, sulfuric acid.The reaction is generally conducted using an organic solvent. As oneskilled in the art will realize, dehydration reactions may be conductedin a wide variety of solvents in a temperature range generally betweenabout 0 and 200° C., more preferably between about 0 and 100° C.). Forthe dehydration in the method of Scheme 8, a solvent comprising aceticacid and temperatures of about 65° C. are preferred. Carboxylic estercompounds can be converted to carboxylic acid compounds by numerousmethods including nucleophilic cleavage under anhydrous conditions orhydrolytic methods involving the use of either acids or bases (see T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nded., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a reviewof methods). For the method of Scheme 8, base-catalyzed hydrolyticmethods are preferred. Suitable bases include alkali metal (such aslithium, sodium or potassium) hydroxides. For example, the ester can bedissolved in a mixture of water and an alcohol such as ethanol. Upontreatment with sodium hydroxide or potassium hydroxide, the ester issaponified to provide the sodium or potassium salt of the carboxylicacid. Acidification with a strong acid, such as hydrochloric acid orsulfuric acid, yields the carboxylic acid of Formula 4. The carboxylicacid can be isolated by methods known to those skilled in the art,including crystallization, extraction and distillation.

[0078] Compounds of Formula 15 can be prepared by the method outlined inScheme 9.

[0079] Treatment of a hydrazine compound of Formula 18 with a ketone ofFormula 19 in a solvent such as water, methanol or acetic acid gives thehydrazone of Formula 20. One skilled in the art will recognize that thisreaction may require catalysis by an optional acid and may also requireelevated temperatures depending on the molecular substitution pattern ofthe hydrazone of Formula 20. Reaction of the hydrazone of Formula 20with the compound of Formula 21 in a suitable organic solvent such as,for example but not limitation, dichloromethane or tetrahydrofuran inthe presence of an acid scavenger such as triethylamine provides thecompound of Formula 15. The reaction is usually conducted at atemperature between about 0 and 100° C. Further experimental details forthe method of Scheme 9 are illustrated in Example 7. Hydrazine compoundsof Formula 18 can be prepared by standard methods, such as by contactingthe corresponding halo compound of Formula 11 with hydrazine.

[0080] As an alternative to the method illustrated in Scheme 6,pyrazolecarboxylic acids of Formula 4 wherein R³ is Cl or Br can also beprepared by the method outlined in Scheme 10.

[0081] Oxidization of the compound of Formula 22 optionally in thepresence of acid to give the compound of Formula 17 followed byconversion of the carboxylic ester function to the carboxylic acidprovides the compound of Formula 4. The oxidizing agent can be hydrogenperoxide, organic peroxides, potassium persulfate, sodium persulfate,ammonium persulfate, potassium monopersulfate (e.g., Oxone®) orpotassium permanganate. To obtain complete conversion, at least oneequivalent of oxidizing agent versus the compound of Formula 22 shouldbe used, preferably between about one to two equivalents. This oxidationis typically carried out in the presence of a solvent. The solvent canbe an ether, such as tetrahydrofuran, p-dioxane and the like, an organicester, such as ethyl acetate, dimethyl carbonate and the like, or apolar aprotic organic such as N,N-dimethylformamide, acetonitrile andthe like. Acids suitable for use in the oxidation step include inorganicacids, such as sulfuric acid, phosphoric acid and the like, and organicacids, such as acetic acid, benzoic acid and the like. The acid, whenused, should be used in greater than 0.1 equivalents versus the compoundof Formula 22. To obtain complete conversion, one to five equivalents ofacid can be used. The preferred oxidant is potassium persulfate and theoxidation is preferably carried out in the presence of sulfuric acid.The reaction can be carried out by mixing the compound of Formula 22 inthe desired solvent and, if used, the acid. The oxidant can then beadded at a convenient rate. The reaction temperature is typically variedfrom as low as about 0° C. up to the boiling point of the solvent inorder to obtain a reasonable reaction time to complete the reaction,preferably less than 8 hours. The desired product, a compound of Formula17 can be isolated by methods known to those skilled in the art,including crystallization, extraction and distillation. Methods suitablefor converting the ester of Formula 17 to the carboxylic acid of Formula4 are already described for Scheme 8. Further experimental details forthe method of Scheme 10 are illustrated in Examples 8 and 9.

[0082] Compounds of Formula 22 can be prepared from correspondingcompounds of Formula 23 as shown in Scheme 11.

[0083] Treatment of a compound of Formula 23 with a halogenatingreagent, usually in the presence of a solvent, affords the correspondinghalo compound of Formula 22. Halogenating reagents that can be usedinclude phosphorus oxyhalides, phosphorus trihalides, phosphoruspentahalides, thionyl chloride, dihalotrialkylphophoranes,dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred arephosphorus oxyhalides and phosphorus pentahalides. To obtain completeconversion, at least 0.33 equivalents of phosphorus oxyhalide versus thecompound of Formula 23 should be used, preferably between about 0.33 and1.2 equivalents. To obtain complete conversion, at least 0.20equivalents of phosphorus pentahalide versus the compound of Formula 23should be used, preferably between about 0.20 and 1.0 equivalents.Compounds of Formula 23 wherein R⁶ is C₁-C₄ alkyl are preferred for thisreaction. Typical solvents for this halogenation include halogenatedalkanes, such as dichloromethane, chloroform, chlorobutane and the like,aromatic solvents, such as benzene, xylene, chlorobenzene and the like,ethers, such as tetrahydrofuran, p-dioxane, diethyl ether, and the like,and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide,and the like. Optionally, an organic base, such as triethylamine,pyridine, N,N-dimethylaniline or the like, can be added. Addition of acatalyst, such as N,N-dimethylformamide, is also an option. Preferred isthe process in which the solvent is acetonitrile and a base is absent.Typically, neither a base nor a catalyst is required when acetonitrilesolvent is used. The preferred process is conducted by mixing thecompound of Formula 23 in acetonitrile. The halogenating reagent is thenadded over a convenient time, and the mixture is then held at thedesired temperature until the reaction is complete. The reactiontemperature is typically between 20° C. and the boiling point ofacetonitrile, and the reaction time is typically less than 2 hours. Thereaction mass is then neutralized with an inorganic base, such as sodiumbicarbonate, sodium hydroxide and the like, or an organic base, such assodium acetate. The desired product, a compound of Formula 22, can beisolated by methods known to those skilled in the art, includingcrystallization, extraction and distillation.

[0084] Alternatively, compounds of Formula 22 wherein R³ is Br or Cl canbe prepared by treating the corresponding compounds of Formula 22wherein R³ is a different halogen (e.g., Cl for making Formula 22wherein R³ is Br) or a sulfonate group such as p-toluenesulfonate,benzenesulfonate and methanesulfonate with hydrogen bromide or hydrogenchloride, respectively. By this method the R³ halogen or sulfonatesubstituent on the Formula 22 starting compound is replaced with Br orCl from hydrogen bromide or hydrogen chloride, respectively. Thereaction is conducted in a suitable solvent such as dibromomethane,dichloromethane or acetonitrile. The reaction can be conducted at ornear atmospheric pressure or above atmospheric pressure in a pressurevessel. When R³ in the starting compound of Formula 22 is a halogen suchas Cl, the reaction is preferably conducted in such a way that thehydrogen halide generated from the reaction is removed by sparging orother suitable means. The reaction can be conducted between about 0 and100° C., most conveniently near ambient temperature (e.g., about 10 to40° C.), and more preferably between about 20 and 30° C. Addition of aLewis acid catalyst (such as aluminum tribromide for preparing Formula22 wherein R³ is Br) can facilitate the reaction. The product of Formula22 is isolated by the usual methods known to those skilled in the art,including extraction, distillation and crystallization. Further detailsfor this process are illustrated in Example 10.

[0085] Starting compounds of Formula 22 wherein R³ is Cl or Br can beprepared from corresponding compounds of Formula 23 as alreadydescribed. Starting compounds of Formula 22 wherein R³ is a sulfonategroup can likewise be prepared from corresponding compounds of Formula23 by standard methods such as treatment with a sulfonyl chloride (e.g.,p-toluenesulfonyl chloride) and base such as a tertiary amine (e.g.,triethylamine) in a suitable solvent such as dichloromethane; furtherdetails for this process are illustrated in Example 11.

[0086] As an alternative to the method illustrated in Scheme 6,pyrazolecarboxylic acids of Formula 4 wherein R³ is OCH₂CF₃ can also beprepared by the method outlined in Scheme 12.

[0087] In this method, instead of being halogenated as shown in Scheme11, the compound of Formula 23 is oxidized to the compound of Formula17a. The reaction conditions for this oxidation are as already describedfor the conversion of the compound of Formula 22 to the compound ofFormula 17 in Scheme 10.

[0088] The compound of Formula 17a is then alkylated to form thecompound of Formula 17b by contact with an alkylating agent CF₃CH₂X (24)in the presence of a base. In the alkylating agent 24, X is anucleophilic reaction leaving group such as halogen (e.g., Br, I),OS(O)₂CH₃ (methanesulfonate), OS(O)₂CF₃, OS(O)₂Ph-p-CH₃(p-toluenesulfonate), and the like; methanesulfonate works well. Thereaction is conducted in the presence of at least one equivalent of abase. Suitable bases include inorganic bases, such as alkali metal (suchas lithium, sodium or potassium) carbonates and hydroxides, and organicbases, such as triethylamine, diisopropylethylamine and1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conductedin a solvent, which can comprise alcohols, such as methanol and ethanol,halogenated alkanes, such as dichloromethane, aromatic solvents, such asbenzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, andpolar aprotic solvents, such as acetonitrile, such as such asacetonitrile, N,N-dimethylformamide, and the like. Alcohols and polaraprotic solvents are preferred for use with inorganic bases. Potassiumcarbonate as base and acetonitrile as solvent are preferred. Thereaction is generally conducted between about 0 and 150° C., with mosttypically between ambient temperature and 100 ° C. The product ofFormula 17b can be isolated by conventional techniques such asextraction. The ester of Formula 17b can then be converted to thecarboxylic acid of Formula 4 by the methods already described for theconversion of Formula 17 to Formula 4 in Scheme 8. Further experimentaldetails for the method of Scheme 12 are illustrated in Example 12.

[0089] Compounds of Formula 23 can be prepared from compounds of Formula18 as outlined in Scheme 13.

[0090] In this method, a hydrazine compound of Formula 18 is contactedwith a compound of Formula 25 (a fumarate ester or maleate ester or amixture thereof may be used) in the presence of a base and a solvent.The base is typically a metal alkoxide salt, such as sodium methoxide,potassium methoxide, sodium ethoxide, potassium ethoxide, potassiumtert-butoxide, lithium tert-butoxide, and the like. Greater than 0.5equivalents of base versus the compound of Formula 18 should be used,preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalentsof the compound of Formula 25 should be used, preferably between 1.0 to1.3 equivalents. Polar protic and polar aprotic organic solvents can beused, such as alcohols, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferredsolvents are alcohols such as methanol and ethanol. It is especiallypreferred that the alcohol be the same as that making up the fumarate ormaleate ester and the alkoxide base. The reaction is typically conductedby mixing the compound of Formula 18 and the base in the solvent. Themixture can be heated or cooled to a desired temperature and thecompound of Formula 25 added over a period of time. Typically reactiontemperatures are between 0° C. and the boiling point of the solventused. The reaction may be conducted under greater than atmosphericpressure in order to increase the boiling point of the solvent.Temperatures between about 30 and 90° C. are generally preferred. Theaddition time can be as quick as heat transfer allows. Typical additiontimes are between 1 minute and 2 hours. Optimum reaction temperature andaddition time vary depending upon the identities of the compounds ofFormula 18 and Formula 25. After addition, the reaction mixture can beheld for a time at the reaction temperature. Depending upon the reactiontemperature, the required hold time may be from 0 to 2 hours. Typicalhold times are 10 to 60 minutes. The reaction mass then can be acidifiedby adding an organic acid, such as acetic acid and the like, or aninorganic acid, such as hydrochloric acid, sulfuric acid and the like.Depending on the reaction conditions and the means of isolation, the—CO₂R⁶ function on the compound of Formula 23 may be hydrolyzed to—CO₂H; for example, the presence of water in the reaction mixture canpromote such hydrolysis. If the carboxylic acid (—CO₂H) is formed, itcan be converted back to —CO₂R⁶ wherein R⁶ is C₁-C₄ alkyl usingesterification methods well-known in the art. The desired product, acompound of Formula 23, can be isolated by methods known to thoseskilled in the art, such as crystallization, extraction or distillation.

[0091] It is recognized that some reagents and reaction conditionsdescribed above for preparing compounds of Formula 1 may not becompatible with certain functionalities present in the intermediates. Inthese instances, the incorporation of protection/deprotection sequencesor functional group interconversions into the synthesis will aid inobtaining the desired products. The use and choice of the protectinggroups will be apparent to one skilled in chemical synthesis (see, forexample, T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd ed.; Wiley: N.Y., 1991). One skilled in the art willrecognize that, in some cases, after the introduction of a given reagentas it is depicted in any individual scheme, it may be necessary toperform additional routine synthetic steps not described in detail tocomplete the synthesis of compounds of Formula 1. One skilled in the artwill also recognize that it may be necessary to perform a combination ofthe steps illustrated in the above schemes in an order other than thatimplied by the particular sequence presented to prepare the compounds ofFormula 1.

[0092] It is believed that one skilled in the art using the precedingdescription can utilize the present invention to its fullest extent. Thefollowing Examples are, therefore, to be construed as merelyillustrative, and not limiting of the disclosure in any way whatsoever.Steps in the following Examples illustrate a procedure for each step inan overall synthetic transformation, and the starting material for eachstep may not have necessarily been prepared by a particular preparativerun whose procedure is described in other Examples or Steps. Percentagesare by weight except for chromatographic solvent mixtures or whereotherwise indicated. Parts and percentages for chromatographic solventmixtures are by volume unless otherwise indicated. ¹H NMR spectra arereported in ppm downfield from tetramethylsilane; “s” means singlet, “d”means doublet, “t” means triplet, “q” means quartet, “m” meansmultiplet, “dd” means doublet of doublets, “dt” means doublet oftriplets, and “br s” means broad singlet.

EXAMPLE 1 Preparation ofN-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0093] Step A: Preparation of 2-amino-3-methyl-5-chlorobenzoic acid

[0094] To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g,99.2 mmol) in N,N-dimethylformamide (50 mL) was addedN-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture washeated to 100° C. for 30 minutes. The heat was removed, the reaction wascooled to room temperature and let stand overnight. The reaction mixturewas then slowly poured into ice-water (250 mL) to precipitate a whitesolid. The solid was filtered and washed four times with water and thentaken up in ethyl acetate (900 mL). The ethyl acetate solution was driedover magnesium sulfate, evaporated under reduced pressure and theresidual solid was washed with ether to afford the desired intermediateas a white solid (13.9 g).

[0095]¹H NMR (DMSO-d₆) δ 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).

[0096] Step B: Preparation of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

[0097] To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dryN,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g,1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours.The reaction was cooled to 100° C. and filtered through Celite®diatomaceous filter aid to remove solids. N,N-Dimethylformamide andexcess dichloropyridine were removed by distillation at atomosphericpressure. Distillation of the product at reduced pressure (b.p. 139-141°C., 7 mm) afforded the desired intermediate as a clear yellow oil (113.4g).

[0098]¹H NMR (CDCl₃) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15(s, 1H), 8.45 (d, 1H).

[0099] Step C: Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0100] To a solution of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (i.e. thepyrazole product from Step B) (105.0 g, 425 mmol) in dry tetrahydrofuran(700 mL) at −75° C. was added via cannula a −30° C. solution of lithiumdiisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deepred solution was stirred for 15 minutes, after which time carbon dioxidewas bubbled through at −63° C. until the solution became pale yellow andthe exothermicity ceased. The reaction was stirred for an additional 20minutes and then quenched with water (20 mL). The solvent was removedunder reduced pressure, and the reaction mixture partitioned betweenether and 0.5 N aqueous sodium hydroxide solution. The aqueous extractswere washed with ether (3×), filtered through Celite® diatomaceousfilter aid to remove residual solids, and then acidified to a pH ofapproximately 4, at which point an orange oil formed. The aqueousmixture was stirred vigorously and additional acid was added to lowerthe pH to 2.5-3. The orange oil congealed into a granular solid, whichwas filtered, washed successively with water and 1 N hydrochloric acid,and dried under vacuum at 50° C. to afford the title product as anoff-white solid (130 g). (Product from another run following similarprocedure melted at 175-176° C.)

[0101]¹H NMR (DMSO-d₆) δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60(d, 1H).

[0102] Step D: Preparation of6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0103] To a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) inacetonitrile (75 mL) was added dropwise a mixture of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (i.e. the carboxylic acid product of Step C) (7.5 g, 27.0 mmol) andtriethylamine (3.75 mL, 27.0 mmol) in acetonitrile (75 mL) at 0-5° C.The reaction temperature was then maintained at 0° C. throughoutsuccessive addition of reagents. After stirring for 20 minutes,2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Step A)(5.1 g, 27.0 mmol) was added and stirring was continued for anadditional 5 minutes. A solution of triethylamine (7.5 mL, 54.0 mmol) inacetonitrile (15 mL) was then added dropwise, and the reaction mixturewas stirred 45 minutes, followed by the addition of methanesulfonylchloride (2.2 mL, 28.3 mmol). The reaction mixture was then warmed toroom temperature and stirred overnight. Approximately 75 mL of water wasthen added to precipitate 5.8 g of a yellow solid. An additional 1 g ofproduct was isolated by extraction from the filtrate to provide a totalof 6.8 g of the title compound as a yellow solid.

[0104]¹H NMR (CDCl₃) δ 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m,2H), 7.99 (m,2H), 8.58 (d, 1H).

[0105] Step E: Preparation ofN-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0106] To a solution of6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4one(i.e. the benzoxazinone product of Step D) (5.0 g, 11.3 mmol) intetrahydrofuran (35 mL) was added dropwise isopropylamine (2.9 mL, 34.0mmol) in tetrahydrofuran (10 mL) at room temperature. The reactionmixture was then warmed until all solids had dissolved and stirred anadditional five minutes, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The tetrahydrofuransolvent was evaporated under reduced pressure, and the residual solidwas purified by chromatography on silica gel, followed by triturationwith ether/hexane to afford the title compound, a compound of thepresent invention, as a solid (4.6 g), melting at 195-196° C.

[0107]¹H NMR (CDCl₃) δ 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95(br d, 1H), 7.1-7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H),8.50 (d, 1H), 10.24 (br s, 1H).

EXAMPLE 2 Preparation ofN-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0108] To a solution of6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4one(i.e. the benzoxazinone product of Example 1, Step D) (4.50 g, 10.18mmol) in tetrahydrofuran (THF; 70 mL) was added methylamine (2.0 Msolution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture wasstirred at room temperature for 5 minutes. The tetrahydrofuran solventwas evaporated under reduced pressure and the residual solid waspurified by chromatography on silica gel to afford 4.09 g of the titlecompound, a compound of the present invention, as a white solid meltingat 185-186° C.

[0109]¹H NMR (DMSO-d₆) δ 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46(dd, 1H), 7.65 (dd, 1H), 7.74 (s, 1H), 8.21 (d, 1H), 8.35 (br q, 1H),8.74 (d, 1H), 10.39 (s, 1H).

EXAMPLE 3 Preparation of3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0110] Step A: Preparation of3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide

[0111] To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol)in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise asolution of 2.5 M n-butyllithium (472 mL, 1.18 mol) in hexane whilemaintaining the temperature below −65° C. Upon completion of theaddition the reaction mixture was maintained at −78° C. for anadditional 45 minutes, after which time a solution of hexachloroethane(279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. Thereaction mixture was maintained for an hour at −78° C., warmed to −20°C. and then quenched with water (1 L). The reaction mixture wasextracted with methylene chloride (4×500 mL); the organic extracts weredried over magnesium sulfate and concentrated. The crude product wasfurther purified by chromatography on silica gel using methylenechloride as eluent to afford the title product compound as a yellow oil(160 g).

[0112]¹H NMR (CDCl₃) δ 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, 1H).

[0113] Step B: Preparation of 3-chloropyrazole

[0114] To trifluoroacetic acid (290 mL) was added dropwise3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (i.e. the chloropyrazoleproduct of Step A) (160 g), and the reaction mixture was stirred at roomtemperature for 1.5 hrs and then concentrated at reduced pressure. Theresidue was taken up in hexane, insoluble solids were filtered off, andthe hexane was concentrated to afford the crude product as an oil. Thecrude product was further purified by chromatography on silica gel usingether/hexane (40:60) as eluent to afford the title product as a yellowoil (64.44 g).

[0115]¹H NMR (CDCl₃) δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H).

[0116] Step C: Preparation of3-chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine

[0117] To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) inN,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g,1.06 mol), and the reaction mixture was then heated to 100° C. for 36hours. The reaction mixture was cooled to room temperature and slowlypoured into ice water. The precipitated solids were filtered and washedwith water. The solid filter cake was taken up in ethyl acetate, driedover magnesium sulfate and concentrated. The crude solid waschromatographed on silica gel using 20% ethyl acetate/hexane as eluentto afford the title product as a white solid (39.75 g).

[0118]¹H NMR (CDCl₃) δ 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09(s, 1H), 8.41 (d, 1H).

[0119] Step D: Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0120] To a solution of 3-chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine(i.e. the pyrazole product of Step C) (39.75 g, 186 mmol) in drytetrahydrofuran (400 mL) at −78° C. was added dropwise a solution of 2.0M lithium diisopropylamide (93 mL, 186 mmol) in tetrahydrofuran. Carbondioxide was bubbled through the amber solution for 14 minutes, afterwhich time the solution became pale brownish-yellow. The reaction wasmade basic with 1 N aqueous sodium hydroxide solution and extracted withether (2×500 mL). The aqueous extracts were acidified with 6 Nhydrochloric acid and extracted with ethyl acetate (3×500 mL). The ethylacetate extracts were dried over magnesium sulfate and concentrated toafford the title product as an off-white solid (42.96 g). (Product fromanother run following a similar procedure melted at 198-199° C.)

[0121]¹H NMR (DMSO-d₆) δ 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51(d, 1H).

[0122] Step E: Preparation of6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0123] To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) inacetonitrile (150 mL) was added dropwise a mixture of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the carboxylic acid product of Step D) (15.0 g, 58.16 mmol) andtriethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C.The reaction mixture was then stirred for 30 minutes at 0° C. Then,2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1,Step A) (10.79 g, 58.16 mmol) was added, and stirring was continued foran additional 10 minutes. A solution of triethylamine (11.77 g, 116.5mmol) in acetonitrile was then added dropwise while keeping thetemperature below 10° C. The reaction mixture was stirred 60 minutes at0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added.The reaction mixture was then warmed to room temperature and stirred foran additional 2 hours. The reaction mixture was then concentrated, andthe crude product was chromatographed on silica gel using methylenechloride as eluent to afford the title product as a yellow solid (9.1g).

[0124]¹H NMR (CDCl₃) δ1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d,2H), 8.56 (d, 1H).

[0125] Step F: Preparation of3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0126] To a solution of6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one(e.g, the benzoxazinone product of Step E) (6.21 g, 15.21 mmol) intetrahydrofuran (100 mL) was added isopropylamine (4.23 g, 72.74 mmol)and the reaction mixture was then heated to 60° C., stirred for 1 hourand then cooled to room temperature. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was purifiedby chromatography on silica gel to afford the title compound, a compoundof the present invention, as a white solid (5.05 g) melting at 173-175°C.

[0127]¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97(d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83(d, 1H), 8.43 (d, 1H), 10.15 (br s, 1H).

EXAMPLE 4 Preparation of3-chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0128] To a solution of6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Example 3, Step E) (6.32 g, 15.47mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solutionin THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60°C., stirred for 1 hour and then cooled to room temperature. Thetetrahydrofuran solvent was evaporated under reduced pressure, and theresidual solid was purified by chromatography on silica gel to affordthe title compound, a compound of the present invention, as a whitesolid (4.57 g) melting at 225-226° C.

[0129]¹H NMR (CDCl₃) δ 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, 1H), 7.06(s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m, 1H), 7.83 (d, 1H), 8.42(d, 1H), 10.08 (br s, 1H).

EXAMPLE 5 Preparation of3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0130] Step A: Preparation of3-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide

[0131] To a solution of N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol)in dry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solutionof n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) whilemaintaining the temperature below −60° C. A thick solid formed duringthe addition. Upon completion of the addition the reaction mixture wasmaintained for an additional 15 minutes, after which time a solution of1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150mL) was added dropwise while maintaining the temperature below −70° C.The reaction mixture turned a clear orange; stirring was continued foran additional 15 minutes. The −78° C. bath was removed and the reactionwas quenched with water (600 mL). The reaction mixture was extractedwith methylene chloride (4×), and the organic extracts were dried overmagnesium sulfate and concentrated. The crude product was furtherpurified by chromatography on silica gel using methylene chloride-hexane(50:50) as eluent to afford the title product as a clear colorless oil(57.04 g).

[0132]¹H NMR (CDCl₃) δ3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

[0133] Step B: Preparation of 3-bromopyrazole

[0134] To trifluoroacetic acid (70 mL) was slowly added3-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide (i.e. the bromopyrazoleproduct of Step A) (57.04 g). The reaction mixture was stirred at roomtemperature for 30 minutes and then concentrated at reduced pressure.The residue was taken up in hexane, insoluble solids were filtered off,and the hexane was evaporated to afford the crude product as an oil. Thecrude product was further purified by chromatography on silica gel usingethyl acetate/dichloromethane (10:90) as eluent to afford an oil. Theoil was taken up in dichloromethane, neutralized with aqueous sodiumbicarbonate solution, extracted with methylene chloride (3×), dried overmagnesium sulfate and concentrated to afford the title product as awhite solid (25.9 g), m.p. 61-64° C.

[0135]¹H NMR (CDCl₃) δ 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H).

[0136] Step C: Preparation of2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine

[0137] To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dryN,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352mmol), and the reaction mixture was heated to 125° C. for 18 hours. Thereaction mixture was cooled to room temperature and poured into icewater (800 mL). A precipitate formed. The precipitated solids werestirred for 1.5 hrs, filtered and washed with water (2×100 mL). Thesolid filter cake was taken up in methylene chloride and washedsequentially with water, 1N hydrochloric acid, saturated aqueous sodiumbicarbonate solution, and brine. The organic extracts were then driedover magnesium sulfate and concentrated to afford 39.9 g of a pinksolid. The crude solid was suspended in hexane and stirred vigorouslyfor 1 hr. The solids were filtered, washed with hexane and dried toafford the title product as an off-white powder (30.4 g) determined tobe >94% pure by NMR. This material was used without fbrther purificationin Step D.

[0138]¹H NMR (CDCl₃) δ 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05(s, 1H), 8.43 (d, 1H).

[0139] Step D: Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0140] To a solution of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine(i.e. the pyrazole product of Step C) (30.4 g, 118 mmol) in drytetrahydrofuran (250 mL) at −76° C. was added dropwise a solution oflithium diisopropylamide (118 mmol) in tetrahydrofuran at such a rate asto maintain the temperature below −71° C. The reaction mixture wasstirred for 15 minutes at −76° C., and carbon dioxide was then bubbledthrough for 10 minutes, causing warming to −57° C. The reaction mixturewas warmed to −20° C. and quenched with water. The reaction mixture wasconcentrated and then taken up in water (1 L) and ether (500 mL), andthen aqueous sodium hydroxide solution (1 N, 20 mL) was added. Theaqueous extracts were washed with ether and acidified with hydrochloricacid. The precipitated solids were filtered, washed with water and driedto afford the title product as a tan solid (27.7 g). (Product fromanother run following similar procedure melted at 200-201° C.)

[0141]¹H NMR (DMSO-d₆) δ 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56(d, 1H).

[0142] Step E: Preparation of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

[0143] A procedure analogous to that of Example 1, Step E was used toconvert 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid(i.e. the pyrazolecarboxylic acid product of Example 5, Step D) (1.5 g,4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the productof Example 1 Step A) (0.92 g, 4.96 mmol) to the title product as a solid(1.21 g).

[0144]¹H NMR (CDCl₃) δ 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95(d, 1H), 8.04 (m, 1H), 8.25 (s, 1H), 8.26 (d, 1H).

[0145] Step F: Preparation of3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0146] To a solution of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Step E) (0.20 g, 0.44 mmol) intetrahydrofuran was added isopropylamine (0.122 mL, 1.42 mmol), and thereaction mixture was heated to 60° C. for 90 minutes and then cooled toroom temperature. The tetrahydrofuran solvent was evaporated underreduced pressure, and the residual solid was triturated with ether,filtered, and dried to afford the title compound, a compound of thepresent invention, as a solid (150 mg), m.p. 159-161° C.

[0147]¹H NMR (CDCl₃) δ 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99(m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41(d, 1H).

EXAMPLE 6 Preparation of3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0148] To a solution of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazinone(i.e. the benzoxazinone product of Example 5, Step E) (0.20 g, 0.44mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF,0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60° C. for90 minutes and then cooled to room temperature. The tetrahydrofuransolvent was evaporated under reduced pressure, and the residual solidwas triturated with ether, filtered, and dried to afford the titlecompound, a compound of the present invention, as a solid (40 mg), m.p.162-164° C.

[0149] 1H NMR (CDCl₃) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10(s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).

[0150] The following Example 7 illustrates an alternative preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid, which can be used to prepare, for example,N-[4chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideandN-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 1 and 2.

EXAMPLE 7 Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0151] Step A: Preparation of 3-chloro-2(1H)-pyridinone(2,2,2-trifluoro-1-methylethylidene)hydrazone

[0152] 1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to3-chloro-2(1H)-pyridinone hydrazone (alternatively named(3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. Afterthe addition was complete, the mixture was stirred for about 10 minutes.The solvent was removed under reduced pressure and the mixturepartitioned between ethyl acetate (100 mL) and saturated aqueous sodiumcarbonate solution (100 mL). The organic layer was dried and evaporated.Chromatography on silica gel (eluted with ethyl acetate) gave theproduct as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (aftercrystallization from ethyl acetate/hexanes).

[0153] IR (nujol) ν 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196,1158, 1100, 1032, 992, 800 cm⁻¹. ¹H NMR (CDCl₃) δ 2.12 (s, 3H),6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-8.32 (m, 2H). MS m/z 237(M⁺).

[0154] Step B: Preparation of ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazide(alternatively named ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazine)

[0155] Triethylamine (20.81 g, 0.206 mol) was added to3-chloro-2(1H)-pyridinone (2,2,2-trifluoro-1-methylethylidene)hydrazone(i.e. the product of Step A) (32.63 g, 0.137 mol) in dichloromethane (68mL) at 0° C. Ethyl chlorooxoacetate (18.75 g, 0.137 mol) indichloromethane (69 mL) was added dropwise to the mixture at 0° C. Themixture was allowed to warm to 25° C. over about 2 hours. The mixturewas cooled to 0° C. and a further portion of ethyl chlorooxoacetate(3.75 g, 27.47 mmol) in dichloromethane (14 mL) was added dropwise.After about an additional 1 hour, the mixture was diluted withdichloromethane (about 450 mL), and the mixture was washed with water(2×150 mL). The organic layer was dried and evaporated. Chromatographyon silica gel (eluted with 1:1 ethyl acetate-hexanes) gave the productas a solid (42.06 g, 90% yield), m.p. 73.0-73.5° C. (aftercrystallization from ethyl acetate/hexanes).

[0156] IR (nujol) ν 1751, 1720, 1664, 1572, 1417, 1361, 1330, 1202,1214, 1184, 1137, 1110, 1004, 1043, 1013, 942, 807, 836 cm⁻¹. ¹H NMR(DMSO-d₆, 115° C.) 1.19 (t, 3H), 1.72 (br s, 3H), 4.25 (q, 2H), 7.65(dd, J=8.3 4.7 Hz, 1H), 8.20 (dd, J=7.6, 1.5 Hz, 1H), 8.55 (d, J=3.6 Hz,1H). MS m/z 337 (M⁺).

[0157] Step C: Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0158] Ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methyl-ethylidene)hydrazide(i.e. the product of Step B) (5 g, 14.8 mmol) in dimethyl sulfoxide (25mL) was added to tetrabutylammonium fluoride hydrate (10 g) in dimethylsulfoxide (25 mL) over 8 hours. When the addition was complete, themixture was poured into acetic acid (3.25 g) in water (25 mL). Afterstirring at 25° C. overnight, the mixture was then extracted withtoluene (4×25 mL), and the combined toluene extracts were washed withwater (50 mL), dried and evaporated to give a solid. Chromatography onsilica gel (eluted with 1:2 ethyl acetate-hexanes) gave the product as asolid (2.91 g, 50% yield, containing about 5% of3-chloro-2(1H)-pyridinone(2,2,2-trifluoro-1-methylethylidene)hydrazone), m.p. 78-78.5° C. (afterrecrystallization from ethyl acetate/hexanes).

[0159] IR (nujol) ν 3403, 1726, 1618, 1582, 1407, 1320, 1293, 1260,1217, 1187, 1150, 1122, 1100, 1067, 1013, 873, 829 cm⁻¹. ¹H NMR (CDCl₃)δ 1.19 (s, 3H), 3.20 (½ of ABZ pattern, J=18 Hz, 1H), 3.42 (½ of ABZpattern, J=18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, J=7.9, 4.9 Hz, 1H), 7.74(dd, J=7.7, 1.5 Hz, 1H), 8.03 (dd, J=4.7, 1.5 Hz, 1H). MS m/z 319 (M⁺).

[0160] Step D: Preparation of ethyl1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0161] Sulfuric acid (concentrated, 2 drops) was added to ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) andthe mixture was warmed to 65° C. for about 1 hour. The mixture wasallowed to cool to 25° C. and most of the acetic acid was removed underreduced pressure. The mixture was partitioned between saturated aqueoussodium carbonate solution (100 mL) and ethyl acetate (100 mL). Theaqueous layer was further extracted with ethyl acetate (100 mL). Thecombined organic extracts were dried and evaporated to give the productas an oil (0.66 g, 77% yield).

[0162] IR (neat) ν 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277,1236, 1135, 1082, 1031, 973, 842, 802 cm⁻¹. ¹H NMR (CDCl₃) δ 1.23 (t,3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd, J=8.1, 4.7 Hz, 1H), 7.94 (dd,J=6.6, 2 Hz, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H). MS m/z 319 (M⁺).

[0163] Step E: Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0164] Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) wasadded to ethyl1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(i.e. the product of Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL).After about 30 minutes, the solvent was removed under reduced pressure,and the mixture was dissolved in water (40 mL). The solution was washedwith ethyl acetate (20 mL). The aqueous layer was acidified withconcentrated hydrochloric acid and was extracted with ethyl acetate(3×20 mL). The combined extracts were dried and evaporated to give theproduct as a solid (0.53 g, 93% yield), m.p. 178-179° C. (aftercrystallization from hexanes-ethyl acetate).

[0165] IR (nujol) ν 1711, 1586, 1565, 1550, 1440, 1425, 1292, 1247,1219, 1170, 1135, 1087, 1059, 1031, 972, 843, 816 cm⁻¹. ¹H NMR (DMSO-d₆)δ 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H).

[0166] The following Example 8 illustrates an alternative preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, whichcan be used to prepare, for example,3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideand3-chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 3 and 4.

EXAMPLE 8 Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0167] Step A: Preparation of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (alternativelynamed ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate)

[0168] A 2-L four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged with absolute ethanol (250 mL) and an ethanolic solution ofsodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated toreflux at about 83° C. It was then treated with3-chloro-2(1H)-pyridinone hydrazone (68.0 g, 0.474 mol). The mixture wasre-heated to reflux over a period of 5 minutes. The yellow slurry wasthen treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over aperiod of 5 minutes. The reflux rate increased markedly during theaddition. By the end of the addition all of the starting material haddissolved. The resulting orange-red solution was held at reflux for 10minutes. After being cooled to 65° C., the reaction mixture was treatedwith glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. Themixture was diluted with water (650 mL), causing the precipitate todissolve. The orange solution was cooled in an ice bath. Product beganto precipitate at 28° C. The slurry was held at about 2° C. for 2 hours.The product was isolated via filtration, washed with aqueous ethanol(40%, 3×50 mL), and then air-dried on the filter for about 1 hour. Thetitle product compound was obtained as a highly crystalline, lightorange powder (70.3 g, 55% yield). No significant impurities wereobserved by ¹H NMR.

[0169]¹H NMR (DMSO-d₆) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20(q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18(s, 1H).

[0170] Step B: Preparation of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-chloro-2-pyrazoline-5-carboxylate)

[0171] To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was chargedacetonitrile (1000 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Step A) (91.0 g, 0.337 mol) and phosphorus oxychloride (35.0mL, 0.375 mol). Upon adding the phosphorus oxychloride, the mixtureself-heated from 22 to 25° C. and a precipitate formed. The light-yellowslurry was heated to reflux at 83° C. over a period of 35 minutes,whereupon the precipitate dissolved. The resulting orange solution washeld at reflux for 45 minutes, whereupon it had become black-green. Thereflux condenser was replaced with a distillation head, and 650 mL ofsolvent was removed by distillation. A second 2-L four-necked flaskequipped with a mechanical stirrer was charged with sodium bicarbonate(130 g, 1.55 mol) and water (400 mL). The concentrated reaction mixturewas added to the sodium bicarbonate slurry over a period of 15 minutes.The resulting, two-phase mixture was stirred vigorously for 20 minutes,at which time gas evolution had ceased. The mixture was diluted withdichloromethane (250 mL) and then was stirred for 50 minutes. Themixture was treated with Celite® 545 diatomaceous earth filter aid (11g) and then filtered to remove a black, tarry substance that inhibitedphase separation. Since the filtrate was slow to separate into distinctphases, it was diluted with dichloromethane (200 mL) and water (200 mL)and treated with more Celite® 545 (15 g). The mixture was filtered, andthe filtrate was transferred to a separatory funnel. The heavier, deepgreen organic layer was separated. A rag layer (50 mL) was refilteredand then added to the organic layer. The organic solution (800 mL) wastreated with magnesium sulfate (30 g) and silica gel (12 g), and theslurry was stirred magnetically for 30 minutes. The slurry was filteredto remove the magnesium sulfate and silica gel, which had become deepblue-green. The filter cake was washed with dichloromethane (100 mL).The filtrate was concentrated on a rotary evaporator. The productconsisted of dark amber oil (92.0 g, 93% yield). The only appreciableimpurities observed by ¹H NMR were 1% starting material and 0.7%acetonitrile.

[0172]¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H),4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

[0173] Step C: Preparation of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylate)

[0174] A 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged with ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitrile(1000 mL) and sulfuric acid (98%, 35.0 mL, 0.661 mol). The mixtureself-heated from 22 to 35° C. upon adding the sulfuric acid. After beingstirred for several minutes, the mixture was treated with potassiumpersulfate (140 g, 0.518 mol). The slurry was heated to reflux at 84° C.for 4.5 hours. The resulting orange slurry while still warm (50-65° C.)was filtered to remove a fine, white precipitate. The filter cake waswashed with acetonitrile (50 mL). The filtrate was concentrated to about500 mL on a rotary evaporator. A second 2-L four-necked flask equippedwith a mechanical stirrer was charged with water (1250 mL). Theconcentrated reaction mass was added to the water over a period of about5 minutes. The product was isolated via filtration, washed with aqueousacetonitrile (25%, 3×125 mL), washed once with water (100 mL), and thendried overnight in vacuo at room temperature. The product consisted of acrystalline, orange powder (79.3 g, 82% yield). The only appreciableimpurities observed by ¹H NMR were about 1.9% water and 0.6%acetonitrile.

[0175]¹H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71(dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H).

[0176] Step D: Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid(alternatively named1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylic acid)

[0177] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged with ethyl3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. theproduct of Step C) (97.5% pure, 79.3 g, 0.270 mol), methanol (260 mL),water (140 mL) and sodium hydroxide pellets (13.0 g, 0.325 mol). Uponadding the sodium hydroxide the mixture self-heated from 22 to 35° C.,and the starting material began to dissolve. After being stirred for 45minutes under ambient conditions, all of the starting material haddissolved. The resulting deep orange-brown solution was concentrated toabout 250 mL on a rotary evaporator. The concentrated reaction mixturewas then diluted with water (400 mL). The aqueous solution was extractedwith ether (200 mL). Then the aqueous layer was transferred to a 1-LErlenmeyer flask equipped with a magnetic stirrer. The solution wastreated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol)over a period of about 10 minutes. The product was isolated viafiltration, reslurried with water (2×200 mL), cover washed once withwater (100 mL) and then air-dried on the filter for 1.5 hours. Theproduct consisted of a crystalline, light brown powder (58.1 g, 83%yield). About 0.7% ether was the only appreciable impurity observed by¹H NMR.

[0178]¹H NMR (DMSO-d₆) δ 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56(d, 1H), 13.95 (br s, 1H).

[0179] The following Example 9 illustrates an alternative preparation of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, whichcan be used to prepare, for example,3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideand3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 5 and 6.

EXAMPLE 9 Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0180] Step A1: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-bromo-2-pyrazoline-5-carboxylate) usingphosphorus oxybromide

[0181] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged withacetonitrile (400 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 8, Step A) (50.0 g, 0.185 mol) and phosphorusoxybromide (34.0 g, 0.119 mol). The orange slurry was heated to refluxat 83° C. over a period of 20 minutes. The resulting turbid, orangesolution was held at reflux for 75 minutes, at which time a dense, tan,crystalline precipitate had formed. The reflux condenser was replacedwith a distillation head, and a cloudy, colorless distillate (300 mL)was collected. A second 1-L four-necked flask equipped with a mechanicalstirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water(200 mL). The concentrated reaction mixture was added to the sodiumbicarbonate slurry over a period of 5 minutes. The resulting two-phasemixture was stirred vigorously for 5 minutes, at which time gasevolution had ceased. The mixture was diluted with dichloromethane (200mL) and then was stirred for 75 minutes. The mixture was treated with 5g of Celite® 545 diatomaceous filter aid and then filtered to remove abrown, tarry substance. The filtrate was transferred to a separatoryfunnel. The brown organic layer (400 mL) was separated and then wastreated with magnesium sulfate (15 g) and Darco® G60 activated charcoal(2.0 g). The resulting slurry was stirred magnetically for 15 minutesand then filtered to remove the magnesium sulfate and charcoal. Thegreen filtrate was treated with silica gel (3 g) and stirred for severalminutes. The deep blue-green silica gel was removed by filtration, andthe filtrate was concentrated on a rotary evaporator. The productconsisted of a light amber oil (58.6 g, 95% yield), which crystallizedupon standing. The only appreciable impurity observed by ¹H NMR was 0.3%acetonitrile.

[0182]¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H),4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

[0183] Step A2: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateusing phosphorus pentabromide

[0184] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged withacetonitrile (330 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 8, Step A) (52.0 g, 0.193 mol), and phosphoruspentabromide (41.0 g, 0.0952 mol). The orange slurry was heated toreflux at 84° C. over a period of 20 minutes. The resulting brick-redmixture was held at reflux for 90 minutes, at which time a dense tancrystalline precipitate had formed. The reflux condenser was replacedwith a distillation head, and a cloudy, colorless distillate (220 mL)was collected. A second 1-L four-necked flask equipped with a mechanicalstirrer was charged with sodium bicarbonate (40 g, 0.48 mol) and water(200 mL). The concentrated reaction mixture was added to the sodiumbicarbonate slurry over a period of 5 minutes. The resulting, two-phasemixture was stirred vigorously for 10 minutes, at which time gasevolution had ceased. The mixture was diluted with dichloromethane (200mL) and then was stirred for 10 minutes. The mixture was treated withCelite® 545 diatomaceous filter aid (5 g) and then filtered to remove apurple, tarry substance. The filter cake was washed with dichloromethane(50 mL). The filtrate was transferred to a separatory funnel. Thepurple-red organic layer (400 mL) was separated and then was treatedwith magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.2 g).The slurry was stirred magnetically for 40 minutes. The slurry wasfiltered to remove the magnesium sulfate and charcoal. The filtrate wasconcentrated on a rotary evaporator. The product consisted of a darkamber oil (61.2 g, 95% yield), which crystallized upon standing. Theonly appreciable impurity observed by ¹H NMR was 0.7% acetonitrile.

[0185]¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1E), 3.60 (dd, 1H),4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

[0186] Step B: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylate)

[0187] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged with ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5 dihydro-1H-pyrazole-5-carboxylate(i.e. the product of Steps A1 and A2) (40.2 g, 0.121 mol), acetonitrile(300 mL) and sulfuric acid (98%, 13.0 mL, 0.245 mol). The rnixtureself-heated from 22 to 36° C. upon adding the sulfuric acid. After beingstirred for several minutes, the mixture was treated with potassiumpersulfate (48.0 g, 0.178 mol). The slurry was heated to reflux at 84°C. for 2 hours. The resulting orange slurry while still warm (50-65° C.)was filtered to remove a white precipitate. The filter cake was washedwith acetonitrile (2×50 mL). The filtrate was concentrated to about 200mL on a rotary evaporator. A second 1-L four-necked flask equipped witha mechanical stirrer was charged with water (400 mL). The concentratedreaction mass was added to the water over a period of about 5 minutes.The product was isolated via filtration, washed sequentially withaqueous acetonitrile (20%, 100 mL) and water (75 mL), and was thenair-dried on the filter for 1 hour. The product consisted of acrystalline, orange powder (36.6 g, 90% yield). The only appreciableimpurities observed by ¹H NMR were about 1% of an unknown and 0.5%acetonitrile.

[0188]¹H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72(dd, 1H), 8.39 (d, 1H), 8.59 (d, 1H).

[0189] Step C: Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid(alternatively named1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic acid)

[0190] A 300-mL four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged with ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. theproduct of Step B) (98.5% pure, 25.0 g, 0.0756 mol), methanol (75 mL),water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Uponadding the sodium hydroxide the mixture self-heated from 29 to 34° C.and the starting material began to dissolve. After being stirred for 90minutes under ambient conditions, all of the starting material haddissolved. The resulting dark orange solution was concentrated to about90 mL on a rotary evaporator. The concentrated reaction mixture was thendiluted with water (160 mL). The aqueous solution was extracted withether (100 mL). Then the aqueous layer was transferred to a 500-mLErlenmeyer flask equipped with a magnetic stirrer. The solution wastreated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839mol) over a period of about 10 minutes. The product was isolated viafiltration, reslurried with water (2×40 mL), cover washed once withwater (25 mL), and then air-dried on the filter for 2 hours. The productconsisted of a crystalline, tan powder (20.9 g, 91% yield). The onlyappreciable impurities observed by 1H NMR were about 0.8% of an unknownand 0.7% ether.

[0191]¹H NMR (DMSO-d₆) δ 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H),8.25 (d, 1H), 7.68 (dd, 1H).

[0192] The following Example 10 illustrates an alternative preparationof ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate,which can be used to prepare, for example, ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. productof Example 9, Step B).

EXAMPLE 10 Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylatefrom ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateusing hydrogen bromide

[0193] Hydrogen bromide was passed through a solution of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. product of Example 8, Step B) (8.45 g, 29.3 mmol) indibromomethane (85 mL). After 90 minutes the gas flow was terminated,and the reaction mixture was washed with aqueous sodium bicarbonatesolution (100 mL). The organic phase was dried and evaporated underreduced pressure to give the title product as an oil (9.7 g, 99% yield),which crystallized on standing.

[0194]¹H NMR (CDCl₃) δ 1.19 (t, 3H), 3.24 (½ of AB in ABX pattern,J=9.3, 17.3 Hz, 1H), 3.44 (½ of AB in ABX pattern, J=11.7, 17.3 Hz, 1H),4.18 (q, 2H), 5.25 (X of ABX, 1H, J=9.3, 11.9 Hz), 6.85 (dd, J=4.7, 7.7Hz, 1H), 7.65 (dd, J=1.6, 7.8 Hz, 1H), 8.07 (dd, J=1.6, 4.8 Hz, 1H).

[0195] The following Example 11 illustrates the preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate,which can be used to prepare ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateby procedures similar to that described in Example 10.

EXAMPLE 11 Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

[0196] Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixtureof ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e.the product of Example 8, Step A) (10.0 g, 37.1 mmol) andp-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g,1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. Thereaction mixture was then allowed to warm to room temperature and wasstirred overnight. The mixture was then diluted with dichloromethane(200 mL) and washed with water (3×70 mL). The organic phase was driedand evaporated to leave the title product as an oil (13.7 g, 87% yield),which slowly formed crystals. Product recrystallized from ethylacetate/hexanes melted at 99.5-100° C.

[0197] IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178,1084, 1027, 948, 969, 868, 845 cm⁻¹.

[0198]¹H NMR (CDCl₃) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (½ of AB in ABXpattern, J=17.3, 9 Hz, 1H), 3.33 (½ of AB in ABX pattern, J=17.5, 11.8Hz, 1H), 4.16 (q, 2H), 5.72 (X of ABX, J=9, 11.8 Hz, 1H), 6.79 (dd,J=4.6, 7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.56 (dd, J=1.6, 7.8 Hz,1H), 7.95 (d, J=8.4 Hz, 2H), 8.01 (dd, J=1.4, 4.6 Hz, 1H).

EXAMPLE 12 Preparation ofN-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

[0199] Step A: Preparation of ethyl1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate

[0200] To a suspension of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. productof Example 8, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200mL) was added sulfuric acid (20 g, 200 mmol) in one portion. Thereaction mixture thinned to form a pale green, nearly clear solutionbefore thickening again to form a pale yellow suspension. Potassiumpersulfate (33 g, 120 mmol) was added in one portion, and then thereaction mixture was heated at gentle reflux for 3.5 hours. Aftercooling using an ice bath, a precipitate of white solid was removed byfiltration and discarded. The filtrate was diluted with water (400 mL)and then extracted three times with ethyl ether (700 mL total).Concentration of the combined ether extracts to a reduced volume (75 mL)caused precipitation of an off-white solid (3.75 g), which was collectedby filtration. The ether mother liquor was further concentrated to yielda second crop of an off-white precipitate (4.2 g), which was alsocollected by filtration. An off-white solid also precipitated from theaqueous phase; this solid (4.5 g) was collected by filtration to providea combined total of 12.45 g of the title compound.

[0201]¹H NMR (DMSO-d₆) δ 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6(t, 1H), 8.19 (d, 1H), 8.5 (d, 1H), 10.6 (s, 1H).

[0202] Step B: Preparation of ethyl1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate

[0203] To a suspension of ethyl1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate(i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). Thesuspension was stirred for 15 minutes at 20° C. The stirred suspensionwas then cooled to 5° C., and 2,2,2-trifluoro-ethyltrifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. Thereaction mixture was warmed to room temperature and then heated toreflux, at which time thin layer chromatography showed the reaction tobe complete. Water (25 mL) was added to the reaction mixture, which wasthen extracted with ethyl ether. The ether extract was dried overmagnesium sulfate and concentrated to yield the title product compound(1.05 g) as a pale yellow oil.

[0204]¹H NMR (CDCl₃) δ 1.21 (t, 3H), 4.20 (q, 2H), 4.63 (q, 2H), 6.53(s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H).

[0205] Step C: Preparation of1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylicacid

[0206] To a stirred solution of ethyl1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate(i.e. product of Step B) (0.92 g, 2.8 mmol) in methanol (15 mL) wasadded water (5 mL), which caused the reaction mixture to become cloudy.An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) wasadded dropwise, and the reaction mixture was stirred at room temperaturefor 30 minutes, during which time the reaction mixture became againclear. Water (20 mL) was added and the reaction mixture was extractedwith ethyl ether, which was discarded. The aqueous phase was acidifiedto pH 2 using concentrated hydrochloric acid and then extracted withethyl acetate (50 mL). The ethyl acetate extract, which was washed withwater (20 mL) and brine (20 mL), dried over magnesium sulfate andconcentrated to give the title compound, isolated as a white solid (0.8g).

[0207]¹H NMR (DMSO-d₆) δ 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d,1H), 8.55 (d, 1H), 13.7 (bs, 1H).

[0208] Step D: Preparation of6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[0209] To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e.product of Example 1, Step A) (97 g, 520 mmol) stirred in dry dioxane(750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320mmol) was added dropwise. The reaction mixture exothermically warmedslowly to 42° C., and the solid almost completely dissolved before athick suspension formed again. After the suspension was stirred atambient temperature for 2.5 hours, the title compound was isolated byfiltration, washed with ethyl ether, and dried to yield the titleproduct compound, obtained as a white solid (98 g).

[0210] 1H NMR (DMSO-d₆) δ 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H), 11.2(s, 1H).

[0211] Step E: Preparation of6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0212] To a suspension of1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylicacid (i.e. product of Step C) (7.9 g, 24 mmol) stirred indichloromethane (100 mL) was added N,N-diethylformamide (4 drops).Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over a period of 45minutes. The resulting solution was stirred at room temperature for 4hours and then concentrated under vacuum. The isolated acid chloride wasdissolved in dry acetonitrile (10 mL) and added to a suspension of6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of StepD) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10mL) was added, and the solution heated at reflux 6 hours. After coolingusing an ice bath, a precipitate of white solid (9.15 g) was collected.The ¹H NMR spectrum of the collected precipitate showed peaks consistentwith the title compound and residual6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. Asmall portion of the collected precipitate was recrystallized fromacetonitrile to yield the pure title product melting at 178-180° C.

[0213]¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7(t, 1H), 7.75 (s, 1H), 7.9 (s, 1H), 8.3 (d, 1H), 8.6 (d, 1H).

[0214] Step F: Preparation ofN-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

[0215] To a suspension of the6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one(i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) intetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22mmol) was added dropwise, and the resulting solution was stirred at roomtemperature for 45 minutes. Thin layer chromatography then showed thereaction to be complete. Ethyl ether (100 mL) was added, and thereaction mixture was stirred for 2 hours while a precipitate formed. Theprecipitate was collected by filtration and then recrystallized fromacetonitrile to yield a white solid (0.82 g). A second crop of whitesolid (0.35 g) precipitated from the acetonitrile mother liquor and wascollected by filtration. The initial ether/tetrahydrofuran mother liquorwas concentrated to dryness, and the residual solid was recrystallizedfrom acetonitrile to yield a third crop of white solid (0.95 g). Thethree crops were combined, totaling 2.12 g (after drying) of the titlecompound, isolated as a white solid, melting at 207-208° C.

[0216]¹H NMR (CDCl₃) δ 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15(q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.8 (d,1H), 8.45 (d, 1H), 10.0 (s, 1H).

[0217] Examples 13 and 14 illustrate alternatives to reaction conditionsdescribed in Example 5, Step E and Example 3, Step E, respectively.

EXAMPLE 13 Preparation of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

[0218] Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolvedin acetonitrile (10 mL), and the mixture was cooled to −5° C. A solutionof 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the pyrazolecarboxylic acid product of Example 5, Step D) (3.02 g, 10mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) wasadded dropwise over 5 minutes at −5 to 0° C. A slurry formed during theaddition. The mixture was stirred 5 minutes at this temperature, andthen a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. theproduct of Example 1 Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with moreacetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C.,and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) inacetonitrile (5 mL) was added dropwise over 5 minutes at a temperatureof −5 to 0° C. The reaction mixture was stirred 15 minutes more at thistemperature, then allowed to warm slowly to room temperature, andstirred 4 h. Water (20 mL) was added dropwise, and the mixture wasstirred 15 minutes. Then the mixture was filtered, and the solids werewashed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3mL), and dried under nitrogen to afford the title product as a lightyellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLCof the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peakcorresponding to the title compound and having 95.7% of totalchromatogram peak area. ¹H NMR (DMSO-d₆) 8 1.72 (s, 3H) 7.52 (s, 1H),7.72-7.78 (m, 2H), 7.88 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

EXAMPLE 14 Preparation of6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0219] Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolvedin acetonitrile (10 mL), and the mixture was cooled to −5° C. A solutionof 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the carboxylic acid product of Example 3, Step D) (2.58 g, 10 mmol) andpyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was addeddropwise over 5 minutes at −5 to 0° C. A slurry formed during theaddition. The mixture was stirred 5 minutes at this temperature, andthen 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product fromExample 1, Step A) (1.86 g, 10 mmol) was added all at once. Then asolution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL)was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to0° C. The reaction mixture was stirred 15 minutes at this temperature,then allowed to warm slowly to room temperature, and stirred 4 h. Water(15 mL) was added dropwise, and the mixture was stirred 15 minutes. Thenthe mixture was filtered, and the solids were washed with 2:1acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and driedunder nitrogen to afford the title product as a pale yellow powder, 3.83g (94.0% crude yield), melting at 199-201° C. HPLC of the product usinga Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95%acetonitrile/pH 3 water) showed a major peak corresponding to the titlecompound and having 97.8% of total chromatogram peak area.

[0220]¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H),7.87 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

[0221] By the procedures described herein together with methods known inthe art, the following compounds of Table 1 can be prepared. Thefollowing abbreviations are used in the Tables which follow: t meanstertiary, s means secondary, n means normal, i means iso, Me meansmethyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl, and Bumeans butyl. TABLE 1

R¹ R² R³ R^(4a) R^(4b) R⁵ CH₃ F CF₃ Me H Cl CH₃ F CF₃ Et H Cl CH₃ F CF₃i-Pr H Cl CH₃ F CF₃ t-Bu H Cl CH₃ F CF₃ Me Me Cl CH₃ F CF₃ Me H Br CH₃ FCF₃ Et H Br CH₃ F CF₃ i-Pr H Br CH₃ F CF₃ t-Bu H Br CH₃ F CF₃ Me Me BrCH₃ F Cl Me H Cl CH₃ F Cl Et H Cl CH₃ F Cl i-Pr H Cl CH₃ F Cl t-Bu H ClCH₃ F Cl Me Me Cl CH₃ F Cl Me H Br CH₃ F Cl Et H Br CH₃ F Cl i-Pr H BrCH₃ F Cl t-Bu H Br CH₃ F Cl Me Me Br CH₃ F Br Me H Cl CH₃ F Br Et H ClCH₃ F Br i-Pr H Cl CH₃ F Br t-Bu H Cl CH₃ F Br Me Me Cl CH₃ F Br Me H BrCH₃ F Br Et H Br CH₃ F Br i-Pr H Br CH₃ F Br t-Bu H Br CH₃ F Br Me Me BrCH₃ F OCH₂CF₃ Me H Cl CH₃ F OCH₂CF₃ Et H Cl CH₃ F OCH₂CF₃ i-Pr H Cl CH₃F OCH₂CF₃ t-Bu H Cl CH₃ F OCH₂CF₃ Me Me Cl CH₃ F OCH₂CF₃ Me H Br CH₃ FOCH₂CF₃ Et H Br CH₃ F OCH₂CF₃ i-Pr H Br CH₃ F OCH₂CF₃ t-Bu H Br CH₃ FOCH₂CF₃ Me Me Br CH₃ Cl CF₃ Me H Cl CH₃ Cl CF₃ Et H Cl CH₃ Cl CF₃ i-Pr HCl CH₃ Cl CF₃ t-Bu H Cl CH₃ Cl CF₃ Me Me Cl CH₃ Cl CF₃ Me H Br CH₃ ClCF₃ Et H Br CH₃ Cl CF₃ i-Pr H Br CH₃ Cl CF₃ t-Bu H Br CH₃ Cl CF₃ Me MeBr CH₃ Cl Cl Me H Cl CH₃ Cl Cl Et H Cl CH₃ Cl Cl i-Pr H Cl CH₃ Cl Clt-Bu H Cl CH₃ Cl Cl Me Me Cl CH₃ Cl Cl Me H Br CH₃ Cl Cl Et H Br CH₃ ClCl i-Pr H Br CH₃ Cl Cl t-Bu H Br CH₃ Cl Cl Me Me Br CH₃ Cl Br Me H ClCH₃ Cl Br Et H Cl CH₃ Cl Br i-Pr H Cl CH₃ Cl Br t-Bu H Cl CH₃ Cl Br MeMe Cl CH₃ Cl Br Me H Br CH₃ Cl Br Et H Br CH₃ Cl Br i-Pr H Br CH₃ Cl Brt-Bu H Br CH₃ Cl Br Me Me Br CH₃ Cl OCH₂CF₃ Me H Cl CH₃ Cl OCH₂CF₃ Et HCl CH₃ Cl OCH₂CF₃ i-Pr H Cl CH₃ Cl OCH₂CF₃ t-Bu H Cl CH₃ Cl OCH₂CF₃ MeMe Cl CH₃ Cl OCH₂CF₃ Me H Br CH₃ Cl OCH₂CF₃ Et H Br CH₃ Cl OCH₂CF₃ i-PrH Br CH₃ Cl OCH₂CF₃ t-Bu H Br CH₃ Cl OCH₂CF₃ Me Me Br CH₃ Br CF₃ Me H ClCH₃ Br CF₃ Et H Cl CH₃ Br CF₃ i-Pr H Cl CH₃ Br CF₃ t-Bu H Cl CH₃ Br CF₃Me Me Cl CH₃ Br CF₃ Me H Br CH₃ Br CF₃ Et H Br CH₃ Br CF₃ i-Pr H Br CH₃Br CF₃ t-Bu H Br CH₃ Br CF₃ Me Me Br CH₃ Br Cl Me H Cl CH₃ Br Cl Et H ClCH₃ Br Cl i-Pr H Cl CH₃ Br Cl t-Bu H Cl CH₃ Br Cl Me Me Cl CH₃ Br Cl MeH Br CH₃ Br Cl Et H Br CH₃ Br Cl i-Pr H Br CH₃ Br Cl t-Bu H Br CH₃ Br ClMe Me Br CH₃ Br Br Me H Cl CH₃ Br Br Et H Cl CH₃ Br Br i-Pr H Cl CH₃ BrBr t-Bu H Cl CH₃ Br Br Me Me Cl CH₃ Br Br Me H Br CH₃ Br Br Et H Br CH₃Br Br i-Pr H Br CH₃ Br Br t-Bu H Br CH₃ Br Br Me Me Br CH₃ Br OCH₂CF₃ MeH Cl CH₃ Br OCH₂CF₃ Et H Cl CH₃ Br OCH₂CF₃ i-Pr H Cl CH₃ Br OCH₂CF₃ t-BuH Cl CH₃ Br OCH₂CF₃ Me Me Cl CH₃ Br OCH₂CF₃ Me H Br CH₃ Br OCH₂CF₃ Et HBr CH₃ Br OCH₂CF₃ i-Pr H Br CH₃ Br OCH₂CF₃ t-Bu H Br CH₃ Br OCH₂CF₃ MeMe Br CH₃ I CF₃ Me H Cl CH₃ I CF₃ Et H Cl CH₃ I CF₃ i-Pr H Cl CH₃ I CF₃t-Bu H Cl CH₃ I CF₃ Me Me Cl CH₃ I CF₃ Me H Br CH₃ I CF₃ Et H Br CH₃ ICF₃ i-Pr H Br CH₃ I CF₃ t-Bu H Br CH₃ I CF₃ Me Me Br CH₃ I Cl Me H ClCH₃ I Cl Et H Cl CH₃ I Cl i-Pr H Cl CH₃ I Cl t-Bu H Cl CH₃ I Cl Me Me ClCH₃ I Cl Me H Br CH₃ I Cl Et H Br CH₃ I Cl i-Pr H Br CH₃ I Cl t-Bu H BrCH₃ I Cl Me Me Br CH₃ I Br Me H Cl CH₃ I Br Et H Cl CH₃ I Br i-Pr H ClCH₃ I Br t-Bu H Cl CH₃ I Br Me Me Cl CH₃ I Br Me H Br CH₃ I Br Et H BrCH₃ I Br i-Pr H Br CH₃ I Br t-Bu H Br CH₃ I Br Me Me Br CH₃ I OCH₂CF₃ MeH Cl CH₃ I OCH₂CF₃ Et H Cl CH₃ I OCH₂CF₃ i-Pr H Cl CH₃ I OCH₂CF₃ t-Bu HCl CH₃ I OCH₂CF₃ Me Me Cl CH₃ I OCH₂CF₃ Me H Br CH₃ I OCH₂CF₃ Et H BrCH₃ I OCH₂CF₃ i-Pr H Br CH₃ I OCH₂CF₃ t-Bu H Br CH₃ I OCH₂CF₃ Me Me BrCH₃ CF₃ CF₃ Me H Cl CH₃ CF₃ CF₃ Et H Cl CH₃ CF₃ CF₃ i-Pr H Cl CH₃ CF₃CF₃ t-Bu H Cl CH₃ CF₃ CF₃ Me Me Cl CH₃ CF₃ CF₃ Me H Br CH₃ CF₃ CF₃ Et HBr CH₃ CF₃ CF₃ i-Pr H Br CH₃ CF₃ CF₃ t-Bu H Br CH₃ CF₃ CF₃ Me Me Br CH₃CF₃ Cl Me H Cl CH₃ CF₃ Cl Et H Cl CH₃ CF₃ Cl i-Pr H Cl CH₃ CF₃ Cl t-Bu HCl CH₃ CF₃ Cl Me Me Cl CH₃ CF₃ Cl Me H Br CH₃ CF₃ Cl Et H Br CH₃ CF₃ Cli-Pr H Br CH₃ CF₃ Cl t-Bu H Br CH₃ CF₃ Cl Me Me Br CH₃ CF₃ Br Me H ClCH₃ CF₃ Br Et H Cl CH₃ CF₃ Br i-Pr H Cl CH₃ CF₃ Br t-Bu H Cl CH₃ CF₃ BrMe Me Cl CH₃ CF₃ Br Me H Br CH₃ CF₃ Br Et H Br CH₃ CF₃ Br i-Pr H Br CH₃CF₃ Br t-Bu H Br CH₃ CF₃ Br Me Me Br CH₃ CF₃ OCH₂CF₃ Me H Cl CH₃ CF₃OCH₂CF₃ Et H Cl CH₃ CF₃ OCH₂CF₃ i-Pr H Cl CH₃ CF₃ OCH₂CF₃ t-Bu H Cl CH₃CF₃ OCH₂CF₃ Me Me Cl CH₃ CF₃ OCH₂CF₃ Me H Br CH₃ CF₃ OCH₂CF₃ Et H Br CH₃CF₃ OCH₂CF₃ i-Pr H Br CH₃ CF₃ OCH₂CF₃ t-Bu H Br CH₃ CF₃ OCH₂CF₃ Me Me BrCH₃ Cl Cl n-Pr H Cl CH₃ Cl Cl n-Bu H Cl CH₃ Cl Cl s-Bu H Cl CH₃ Cl Cli-Bu H Cl CH₃ Cl Cl Et Me Cl F F CF₃ Me H Cl F F CF₃ Et H Cl F F CF₃i-Pr H Cl F F CF₃ t-Bu H Cl F F CF₃ Me Me Cl F F CF₃ Me H Br F F CF₃ EtH Br F F CF₃ i-Pr H Br F F CF₃ t-Bu H Br F F CF₃ Me Me Br F F Cl Me H ClF F Cl Et H Cl F F Cl i-Pr H Cl F F Cl t-Bu H Cl F F Cl Me Me Cl F F ClMe H Br F F Cl Et H Br F F Cl i-Pr H Br F F Cl t-Bu H Br F F Cl Me Me BrF F Br Me H Cl F F Br Et H Cl F F Br i-Pr H Cl F F Br t-Bu H Cl F F BrMe Me Cl F F Br Me H Br F F Br Et H Br F F Br i-Pr H Br F F Br t-Bu H BrF F Br Me Me Br F F OCH₂CF₃ Me H Cl F F OCH₂CF₃ Et H Cl F F OCH₂CF₃ i-PrH Cl F F OCH₂CF₃ t-Bu H Cl F F OCH₂CF₃ Me Me Cl F F OCH₂CF₃ Me H Br F FOCH₂CF₃ Et H Br F F OCH₂CF₃ i-Pr H Br F F OCH₂CF₃ t-Bu H Br F F OCH₂CF₃Me Me Br F Cl CF₃ Me H Cl F Cl CF₃ Et H Cl F Cl CF₃ i-Pr H Cl F Cl CF₃t-Bu H Cl F Cl CF₃ Me Me Cl F Cl CF₃ Me H Br F Cl CF₃ Et H Br F Cl CF₃i-Pr H Br F Cl CF₃ t-Bu H Br F Cl CF₃ Me Me Br F Cl Cl Me H Cl F Cl ClEt H Cl F Cl Cl i-Pr H Cl F Cl Cl t-Bu H Cl F Cl Cl Me Me Cl F Cl Cl MeH Br F Cl Cl Et H Br F Cl Cl i-Pr H Br F Cl Cl t-Bu H Br F Cl Cl Me MeBr F Cl Br Me H Cl F Cl Br Et H Cl F Cl Br i-Pr H Cl F Cl Br t-Bu H Cl FCl Br Me Me Cl F Cl Br Me H Br F Cl Br Et H Br F Cl Br i-Pr H Br F Cl Brt-Bu H Br F Cl Br Me Me Br F Cl OCH₂CF₃ Me H Cl F Cl OCH₂CF₃ Et H Cl FCl OCH₂CF₃ i-Pr H Cl F Cl OCH₂CF₃ t-Bu H Cl F Cl OCH₂CF₃ Me Me Cl F ClOCH₂CF₃ Me H Br F Cl OCH₂CF₃ Et H Br F Cl OCH₂CF₃ i-Pr H Br F Cl OCH₂CF₃t-Bu H Br F Cl OCH₂CF₃ Me Me Br F Br CF₃ Me H Cl F Br CF₃ Et H Cl F BrCF₃ i-Pr H Cl F Br CF₃ t-Bu H Cl F Br CF₃ Me Me Cl F Br CF₃ Me H Br F BrCF₃ Et H Br F Br CF₃ i-Pr H Br F Br CF₃ t-Bu H Br F Br CF₃ Me Me Br F BrCl Me H Cl F Br Cl Et H Cl F Br Cl i-Pr H Cl F Br Cl t-Bu H Cl F Br ClMe Me Cl F Br Cl Me H Br F Br Cl Et H Br F Br Cl i-Pr H Br F Br Cl t-BuH Br F Br Cl Me Me Br F Br Br Me H Cl F Br Br Et H Cl F Br Br i-Pr H ClF Br Br t-Bu H Cl F Br Br Me Me Cl F Br Br Me H Br F Br Br Et H Br F BrBr i-Pr H Br F Br Br t-Bu H Br F Br Br Me Me Br F Br OCH₂CF₃ Me H Cl FBr OCH₂CF₃ Et H Cl F Br OCH₂CF₃ i-Pr H Cl F Br OCH₂CF₃ t-Bu H Cl F BrOCH₂CF₃ Me Me Cl F Br OCH₂CF₃ Me H Br F Br OCH₂CF₃ Et H Br F Br OCH₂CF₃i-Pr H Br F Br OCH₂CF₃ t-Bu H Br F Br OCH₂CF₃ Me Me Br F I CF₃ Me H Cl FI CF₃ Et H Cl F I CF₃ i-Pr H Cl F I CF₃ t-Bu H Cl F I CF₃ Me Me Cl F ICF₃ Me H Br F I CF₃ Et H Br F I CF₃ i-Pr H Br F I CF₃ t-Bu H Br F I CF₃Me Me Br F I Cl Me H Cl F I Cl Et H Cl F I Cl i-Pr H Cl F I Cl t-Bu H ClF I Cl Me Me Cl F I Cl Me H Br F I Cl Et H Br F I Cl i-Pr H Br F I Clt-Bu H Br F I Cl Me Me Br F I Br Me H Cl F I Br Et H Cl F I Br i-Pr H ClF I Br t-Bu H Cl F I Br Me Me Cl F I Br Me H Br F I Br Et H Br F I Bri-Pr H Br F I Br t-Bu H Br F I Br Me Me Br F I OCH₂CF₃ Me H Cl F IOCH₂CF₃ Et H Cl F I OCH₂CF₃ i-Pr H Cl F I OCH₂CF₃ t-Bu H Cl F I OCH₂CF₃Me Me Cl F I OCH₂CF₃ Me H Br F I OCH₂CF₃ Et H Br F I OCH₂CF₃ i-Pr H Br FI OCH₂CF₃ t-Bu H Br F I OCH₂CF₃ Me Me Br F CF₃ CF₃ Me H Cl F CF₃ CF₃ EtH Cl F CF₃ CF₃ i-Pr H Cl F CF₃ CF₃ t-Bu H Cl F CF₃ CF₃ Me Me Cl F CF₃CF₃ Me H Br F CF₃ CF₃ Et H Br F CF₃ CF₃ i-Pr H Br F CF₃ CF₃ t-Bu H Br FCF₃ CF₃ Me Me Br F CF₃ Cl Me H Cl F CF₃ Cl Et H Cl F CF₃ Cl i-Pr H Cl FCF₃ Cl t-Bu H Cl F CF₃ Cl Me Me Cl F CF₃ Cl Me H Br F CF₃ Cl Et H Br FCF₃ Cl i-Pr H Br F CF₃ Cl t-Bu H Br F CF₃ Cl Me Me Br F CF₃ Br Me H Cl FCF₃ Br Et H Cl F CF₃ Br i-Pr H Cl F CF₃ Br t-Bu H Cl F CF₃ Br Me Me Cl FCF₃ Br Me H Br F CF₃ Br Et H Br F CF₃ Br i-Pr H Br F CF₃ Br t-Bu H Br FCF₃ Br Me Me Br F CF₃ OCH₂CF₃ Me H Cl F CF₃ OCH₂CF₃ Et H Cl F CF₃OCH₂CF₃ i-Pr H Cl F CF₃ OCH₂CF₃ t-Bu H Cl F CF₃ OCH₂CF₃ Me Me Cl F CF₃OCH₂CF₃ Me H Br F CF₃ OCH₂CF₃ Et H Br F CF₃ OCH₂CF₃ i-Pr H Br F CF₃OCH₂CF₃ t-Bu H Br F CF₃ OCH₂CF₃ Me Me Br Cl F CF₃ Me H Cl Cl F CF₃ Et HCl Cl F CF₃ i-Pr H Cl Cl F CF₃ t-Bu H Cl Cl F CF₃ Me Me Cl Cl F CF₃ Me HBr Cl F CF₃ Et H Br Cl F CF₃ i-Pr H Br Cl F CF₃ t-Bu H Br Cl F CF₃ Me MeBr Cl F Cl Me H Cl Cl F Cl Et H Cl Cl F Cl i-Pr H Cl Cl F Cl t-Bu H ClCl F Cl Me Me Cl Cl F Cl Me H Br Cl F Cl Et H Br Cl F Cl i-Pr H Br Cl FCl t-Bu H Br Cl F Cl Me Me Br Cl F Br Me H Cl Cl F Br Et H Cl Cl F Bri-Pr H Cl Cl F Br t-Bu H Cl Cl F Br Me Me Cl Cl F Br Me H Br Cl F Br EtH Br Cl F Br i-Pr H Br Cl F Br t-Bu H Br Cl F Br Me Me Br Cl F OCH₂CF₃Me H Cl Cl F OCH₂CF₃ Et H Cl Cl F OCH₂CF₃ i-Pr H Cl Cl F OCH₂CF₃ t-Bu HCl Cl F OCH₂CF₃ Me Me Cl Cl F OCH₂CF₃ Me H Br Cl F OCH₂CF₃ Et H Br Cl FOCH₂CF₃ i-Pr H Br Cl F OCH₂CF₃ t-Bu H Br Cl F OCH₂CF₃ Me Me Br Cl Cl CF₃Me H Cl Cl Cl CF₃ Et H Cl Cl Cl CF₃ i-Pr H Cl Cl Cl CF₃ t-Bu H Cl Cl ClCF₃ Me Me Cl Cl Cl CF₃ Me H Br Cl Cl CF₃ Et H Br Cl Cl CF₃ i-Pr H Br ClCl CF₃ t-Bu H Br Cl Cl CF₃ Me Me Br Cl Cl Cl Me H Cl Cl Cl Cl Et H Cl ClCl Cl i-Pr H Cl Cl Cl Cl t-Bu H Cl Cl Cl Cl Me Me Cl Cl Cl Cl Me H Br ClCl Cl Et H Br Cl Cl Cl i-Pr H Br Cl Cl Cl t-Bu H Br Cl Cl Cl Me Me Br ClCl Br Me H Cl Cl Cl Br Et H Cl Cl Cl Br i-Pr H Cl Cl Cl Br t-Bu H Cl ClCl Br Me Me Cl Cl Cl Br Me H Br Cl Cl Br Et H Br Cl Cl Br i-Pr H Br ClCl Br t-Bu H Br Cl Cl Br Me Me Br Cl Cl OCH₂CF₃ Me H Cl Cl Cl OCH₂CF₃ EtH Cl Cl Cl OCH₂CF₃ i-Pr H Cl Cl Cl OCH₂CF₃ t-Bu H Cl Cl Cl OCH₂CF₃ Me MeCl Cl Cl OCH₂CF₃ Me H Br Cl Cl OCH₂CF₃ Et H Br Cl Cl OCH₂CF₃ i-Pr H BrCl Cl OCH₂CF₃ t-Bu H Br Cl Cl OCH₂CF₃ Me Me Br Cl Br CF₃ Me H Cl Cl BrCF₃ Et H Cl Cl Br CF₃ i-Pr H Cl Cl Br CF₃ t-Bu H Cl Cl Br CF₃ Me Me ClCl Br CF₃ Me H Br Cl Br CF₃ Et H Br Cl Br CF₃ i-Pr H Br Cl Br CF₃ t-Bu HBr Cl Br CF₃ Me Me Br Cl Br Cl Me H Cl Cl Br Cl Et H Cl Cl Br Cl i-Pr HCl Cl Br Cl t-Bu H Cl Cl Br Cl Me Me Cl Cl Br Cl Me H Br Cl Br Cl Et HBr Cl Br Cl i-Pr H Br Cl Br Cl t-Bu H Br Cl Br Cl Me Me Br Cl Br Br Me HCl Cl Br Br Et H Cl Cl Br Br i-Pr H Cl Cl Br Br t-Bu H Cl Cl Br Br Me MeCl Cl Br Br Me H Br Cl Br Br Et H Br Cl Br Br i-Pr H Br Cl Br Br t-Bu HBr Cl Br Br Me Me Br Cl Br OCH₂CF₃ Me H Cl Cl Br OCH₂CF₃ Et H Cl Cl BrOCH₂CF₃ i-Pr H Cl Cl Br OCH₂CF₃ t-Bu H Cl Cl Br OCH₂CF₃ Me Me Cl Cl BrOCH₂CF₃ Me H Br Cl Br OCH₂CF₃ Et H Br Cl Br OCH₂CF₃ i-Pr H Br Cl BrOCH₂CF₃ t-Bu H Br Cl Br OCH₂CF₃ Me Me Br Cl I CF₃ Me H Cl Cl I CF₃ Et HCl Cl I CF₃ i-Pr H Cl Cl I CF₃ t-Bu H Cl Cl I CF₃ Me Me Cl Cl I CF₃ Me HBr Cl I CF₃ Et H Br Cl I CF₃ i-Pr H Br Cl I CF₃ t-Bu H Br Cl I CF₃ Me MeBr Cl I Cl Me H Cl Cl I Cl Et H Cl Cl I Cl i-Pr H Cl Cl I Cl t-Bu H ClCl I Cl Me Me Cl Cl I Cl Me H Br Cl I Cl Et H Br Cl I Cl i-Pr H Br Cl ICl t-Bu H Br Cl I Cl Me Me Br Cl I Br Me H Cl Cl I Br Et H Cl Cl I Bri-Pr H Cl Cl I Br t-Bu H Cl Cl I Br Me Me Cl Cl I Br Me H Br Cl I Br EtH Br Cl I Br i-Pr H Br Cl I Br t-Bu H Br Cl I Br Me Me Br Cl I OCH₂CF₃Me H Cl Cl I OCH₂CF₃ Et H Cl Cl I OCH₂CF₃ i-Pr H Cl Cl I OCH₂CF₃ t-Bu HCl Cl I OCH₂CF₃ Me Me Cl Cl I OCH₂CF₃ Me H Br Cl I OCH₂CF₃ Et H Br Cl IOCH₂CF₃ i-Pr H Br Cl I OCH₂CF₃ t-Bu H Br Cl I OCH₂CF₃ Me Me Br Cl CF₃CF₃ Me H Cl Cl CF₃ CF₃ Et H Cl Cl CF₃ CF₃ i-Pr H Cl Cl CF₃ CF₃ t-Bu H ClCl CF₃ CF₃ Me Me Cl Cl CF₃ CF₃ Me H Br Cl CF₃ CF₃ Et H Br Cl CF₃ CF₃i-Pr H Br Cl CF₃ CF₃ t-Bu H Br Cl CF₃ CF₃ Me Me Br Cl CF₃ Cl Me H Cl ClCF₃ Cl Et H Cl Cl CF₃ Cl i-Pr H Cl Cl CF₃ Cl t-Bu H Cl Cl CF₃ Cl Me MeCl Cl CF₃ Cl Me H Br Cl CF₃ Cl Et H Br Cl CF₃ Cl i-Pr H Br Cl CF₃ Clt-Bu H Br Cl CF₃ Cl Me Me Br Cl CF₃ Br Me H Cl Cl CF₃ Br Et H Cl Cl CF₃Br i-Pr H Cl Cl CF₃ Br t-Bu H Cl Cl CF₃ Br Me Me Cl Cl CF₃ Br Me H Br ClCF₃ Br Et H Br Cl CF₃ Br i-Pr H Br Cl CF₃ Br t-Bu H Br Cl CF₃ Br Me MeBr Cl CF₃ OCH₂CF₃ Me H Cl Cl CF₃ OCH₂CF₃ Et H Cl Cl CF₃ OCH₂CF₃ i-Pr HCl Cl CF₃ OCH₂CF₃ t-Bu H Cl Cl CF₃ OCH₂CF₃ Me Me Cl Cl CF₃ OCH₂CF₃ Me HBr Cl CF₃ OCH₂CF₃ Et H Br Cl CF₃ OCH₂CF₃ i-Pr H Br Cl CF₃ OCH₂CF₃ t-Bu HBr Cl CF₃ OCH₂CF₃ Me Me Br Cl Cl Cl n-Pr H Cl Cl Cl Cl n-Bu H Cl Cl ClCl s-Bu H Cl Cl Cl Cl i-Bu H Cl Cl Cl Cl Et Me Cl Br F CF₃ Me H Cl Br FCF₃ Et H Cl Br F CF₃ i-Pr H Cl Br F CF₃ t-Bu H Cl Br F CF₃ Me Me Cl Br FCF₃ Me H Br Br F CF₃ Et H Br Br F CF₃ i-Pr H Br Br F CF₃ t-Bu H Br Br FCF₃ Me Me Br Br F Cl Me H Cl Br F Cl Et H Cl Br F Cl i-Pr H Cl Br F Clt-Bu H Cl Br F Cl Me Me Cl Br F Cl Me H Br Br F Cl Et H Br Br F Cl i-PrH Br Br F Cl t-Bu H Br Br F Cl Me Me Br Br F Br Me H Cl Br F Br Et H ClBr F Br i-Pr H Cl Br F Br t-Bu H Cl Br F Br Me Me Cl Br F Br Me H Br BrF Br Et H Br Br F Br i-Pr H Br Br F Br t-Bu H Br Br F Br Me Me Br Br FOCH₂CF₃ Me H Cl Br F OCH₂CF₃ Et H Cl Br F OCH₂CF₃ i-Pr H Cl Br F OCH₂CF₃t-Bu H Cl Br F OCH₂CF₃ Me Me Cl Br F OCH₂CF₃ Me H Br Br F OCH₂CF₃ Et HBr Br F OCH₂CF₃ i-Pr H Br Br F OCH₂CF₃ t-Bu H Br Br F OCH₂CF₃ Me Me BrBr Cl CF₃ Me H Cl Br Cl CF₃ Et H Cl Br Cl CF₃ i-Pr H Cl Br Cl CF₃ t-Bu HCl Br Cl CF₃ Me Me Cl Br Cl CF₃ Me H Br Br Cl CF₃ Et H Br Br Cl CF₃ i-PrH Br Br Cl CF₃ t-Bu H Br Br Cl CF₃ Me Me Br Br Cl Cl Me H Cl Br Cl Cl EtH Cl Br Cl Cl i-Pr H Cl Br Cl Cl t-Bu H Cl Br Cl Cl Me Me Cl Br Cl Cl MeH Br Br Cl Cl Et H Br Br Cl Cl i-Pr H Br Br Cl Cl t-Bu H Br Br Cl Cl MeMe Br Br Cl Br Me H Cl Br Cl Br Et H Cl Br Cl Br i-Pr H Cl Br Cl Br t-BuH Cl Br Cl Br Me Me Cl Br Cl Br Me H Br Br Cl Br Et H Br Br Cl Br i-Pr HBr Br Cl Br t-Bu H Br Br Cl Br Me Me Br Br Cl OCH₂CF₃ Me H Cl Br ClOCH₂CF₃ Et H Cl Br Cl OCH₂CF₃ i-Pr H Cl Br Cl OCH₂CF₃ t-Bu H Cl Br ClOCH₂CF₃ Me Me Cl Br Cl OCH₂CF₃ Me H Br Br Cl OCH₂CF₃ Et H Br Br ClOCH₂CF₃ i-Pr H Br Br Cl OCH₂CF₃ t-Bu H Br Br Cl OCH₂CF₃ Me Me Br Br BrCF₃ Me H Cl Br Br CF₃ Et H Cl Br Br CF₃ i-Pr H Cl Br Br CF₃ t-Bu H Cl BrBr CF₃ Me Me Cl Br Br CF₃ Me H Br Br Br CF₃ Et H Br Br Br CF₃ i-Pr H BrBr Br CF₃ t-Bu H Br Br Br CF₃ Me Me Br Br Br Cl Me H Cl Br Br Cl Et H ClBr Br Cl i-Pr H Cl Br Br Cl t-Bu H Cl Br Br Cl Me Me Cl Br Br Cl Me H BrBr Br Cl Et H Br Br Br Cl i-Pr H Br Br Br Cl t-Bu H Br Br Br Cl Me Me BrBr Br Br Me H Cl Br Br Br Et H Cl Br Br Br i-Pr H Cl Br Br Br t-Bu H ClBr Br Br Me Me Cl Br Br Br Me H Br Br Br Br Et H Br Br Br Br i-Pr H BrBr Br Br t-Bu H Br Br Br Br Me Me Br Br Br OCH₂CF₃ Me H Cl Br Br OCH₂CF₃Et H Cl Br Br OCH₂CF₃ i-Pr H Cl Br Br OCH₂CF₃ t-Bu H Cl Br Br OCH₂CF₃ MeMe Cl Br Br OCH₂CF₃ Me H Br Br Br OCH₂CF₃ Et H Br Br Br OCH₂CF₃ i-Pr HBr Br Br OCH₂CF₃ t-Bu H Br Br Br OCH₂CF₃ Me Me Br Br I CF₃ Me H Cl Br ICF₃ Et H Cl Br I CF₃ i-Pr H Cl Br I CF₃ t-Bu H Cl Br I CF₃ Me Me Cl Br ICF₃ Me H Br Br I CF₃ Et H Br Br I CF₃ i-Pr H Br Br I CF₃ t-Bu H Br Br ICF₃ Me Me Br Br I Cl Me H Cl Br I Cl Et H Cl Br I Cl i-Pr H Cl Br I Clt-Bu H Cl Br I Cl Me Me Cl Br I Cl Me H Br Br I Cl Et H Br Br I Cl i-PrH Br Br I Cl t-Bu H Br Br I Cl Me Me Br Br I Br Me H Cl Br I Br Et H ClBr I Br i-Pr H Cl Br I Br t-Bu H Cl Br I Br Me Me Cl Br I Br Me H Br BrI Br Et H Br Br I Br i-Pr H Br Br I Br t-Bu H Br Br I Br Me Me Br Br IOCH₂CF₃ Me H Cl Br I OCH₂CF₃ Et H Cl Br I OCH₂CF₃ i-Pr H Cl Br I OCH₂CF₃t-Bu H Cl Br I OCH₂CF₃ Me Me Cl Br I OCH₂CF₃ Me H Br Br I OCH₂CF₃ Et HBr Br I OCH₂CF₃ i-Pr H Br Br I OCH₂CF₃ t-Bu H Br Br I OCH₂CF₃ Me Me BrBr CF₃ CF₃ Me H Cl Br CF₃ CF₃ Et H Cl Br CF₃ CF₃ i-Pr H Cl Br CF₃ CF₃t-Bu H Cl Br CF₃ CF₃ Me Me Cl Br CF₃ CF₃ Me H Br Br CF₃ CF₃ Et H Br BrCF₃ CF₃ i-Pr H Br Br CF₃ CF₃ t-Bu H Br Br CF₃ CF₃ Me Me Br Br CF₃ Cl MeH Cl Br CF₃ Cl Et H Cl Br CF₃ Cl i-Pr H Cl Br CF₃ Cl t-Bu H Cl Br CF₃ ClMe Me Cl Br CF₃ Cl Me H Br Br CF₃ Cl Et H Br Br CF₃ Cl i-Pr H Br Br CF₃Cl t-Bu H Br Br CF₃ Cl Me Me Br Br CF₃ Br Me H Cl Br CF₃ Br Et H Cl BrCF₃ Br i-Pr H Cl Br CF₃ Br t-Bu H Cl Br CF₃ Br Me Me Cl Br CF₃ Br Me HBr Br CF₃ Br Et H Br Br CF₃ Br i-Pr H Br Br CF₃ Br t-Bu H Br Br CF₃ BrMe Me Br Br CF₃ OCH₂CF₃ Me H Cl Br CF₃ OCH₂CF₃ Et H Cl Br CF₃ OCH₂CF₃i-Pr H Cl Br CF₃ OCH₂CF₃ t-Bu H Cl Br CF₃ OCH₂CF₃ Me Me Cl Br CF₃OCH₂CF₃ Me H Br Br CF₃ OCH₂CF₃ Et H Br Br CF₃ OCH₂CF₃ i-Pr H Br Br CF₃OCH₂CF₃ t-Bu H Br Br CF₃ OCH₂CF₃ Me Me Br

[0222] As shown in Scheme 1 and further illustrated in Examples 1-10,the benzoxazines of Formula 2 such as those listed in Table 2 are usefulfor preparing the compounds of Formula 1, including those listed inTable 1. TABLE 2 2

R¹ R² R³ R⁵ CH₃ F CF₃ Cl CH₃ F CF₃ Br CH₃ F Cl Cl CH₃ F Cl Br CH₃ F BrCl CH₃ F Br Br CH₃ F OCH₂CF₃ Cl CH₃ F OCH₂CF₃ Br CH₃ Cl CF₃ Cl CH₃ ClCF₃ Br CH₃ Cl Cl Cl CH₃ Cl Cl Br CH₃ Cl Br Cl CH₃ Cl Br Br CH₃ ClOCH₂CF₃ Cl CH₃ Cl OCH₂CF₃ Br CH₃ Br CF₃ Cl CH₃ Br CF₃ Br CH₃ Br Cl ClCH₃ Br Cl Br CH₃ Br Br Cl CH₃ Br Br Br CH₃ Br OCH₂CF₃ Cl CH₃ Br OCH₂CF₃Br CH₃ I CF₃ Cl CH₃ I CF₃ Br CH₃ I Cl Cl CH₃ I Cl Br CH₃ I Br Cl CH₃ IBr Br CH₃ I OCH₂CF₃ Cl CH₃ I OCH₂CF₃ Br CH₃ CF₃ CF₃ Cl CH₃ CF₃ CF₃ BrCH₃ CF₃ Cl Cl CH₃ CF₃ Cl Br CH₃ CF₃ Br Cl CH₃ CF₃ Br Br CH₃ CF₃ OCH₂CF₃Cl CH₃ CF₃ OCH₂CF₃ Br F F CF₃ Cl F F CF₃ Br F F Cl Cl F F Cl Br F F BrCl F F Br Br F F OCH₂CF₃ Cl F F OCH₂CF₃ Br F Cl CF₃ Cl F Cl CF₃ Br F ClCl Cl F Cl Cl Br F Cl Br Cl F Cl Br Br F Cl OCH₂CF₃ Cl F Cl OCH₂CF₃ Br FBr CF₃ Cl F Br CF₃ Br F Br Cl Cl F Br Cl Br F Br Br Cl F Br Br Br F BrOCH₂CF₃ Cl F Br OCH₂CF₃ Br F I CF₃ Cl F I CF₃ Br F I Cl Cl F I Cl Br F IBr Cl F I Br Br F I OCH₂CF₃ Cl F I OCH₂CF₃ Br F CF₃ CF₃ Cl F CF₃ CF₃ BrF CF₃ Cl Cl F CF₃ Cl Br F CF₃ Br Cl F CF₃ Br Br F CF₃ OCH₂CF₃ Cl F CF₃OCH₂CF₃ Br Cl F CF₃ Cl Cl F CF₃ Br Cl F Cl Cl Cl F Cl Br Cl F Br Cl Cl FBr Br Cl F OCH₂CF₃ Cl Cl F OCH₂CF₃ Br Cl Cl CF₃ Cl Cl Cl CF₃ Br Cl Cl ClCl Cl Cl Cl Br Cl Cl Br Cl Cl Cl Br Br Cl Cl OCH₂CF₃ Cl Cl Cl OCH₂CF₃ BrCl Br CF₃ Cl Cl Br CF₃ Br Cl Br Cl Cl Cl Br Cl Br Cl Br Br Cl Cl Br BrBr Cl Br OCH₂CF₃ Cl Cl Br OCH₂CF₃ Br Cl I CF₃ Cl Cl I CF₃ Br Cl I Cl ClCl I Cl Br Cl I Br Cl Cl I Br Br Cl I OCH₂CF₃ Cl Cl I OCH₂CF₃ Br Cl CF₃CF₃ Cl Cl CF₃ CF₃ Br Cl CF₃ Cl Cl Cl CF₃ Cl Br Cl CF₃ Br Cl Cl CF₃ Br BrCl CF₃ OCH₂CF₃ Cl Cl CF₃ OCH₂CF₃ Br Br F CF₃ Cl Br F CF₃ Br Br F Cl ClBr F Cl Br Br F Br Cl Br F Br Br Br F OCH₂CF₃ Cl Br F OCH₂CF₃ Br Br ClCF₃ Cl Br Cl CF₃ Br Br Cl Cl Cl Br Cl Cl Br Br Cl Br Cl Br Cl Br Br BrCl OCH₂CF₃ Cl Br Cl OCH₂CF₃ Br Br Br CF₃ Cl Br Br CF₃ Br Br Br Cl Cl BrBr Cl Br Br Br Br Cl Br Br Br Br Br Br OCH₂CF₃ Cl Br Br OCH₂CF₃ Br Br ICF₃ Cl Br I CF₃ Br Br I Cl Cl Br I Cl Br Br I Br Cl Br I Br Br Br IOCH₂CF₃ Cl Br I OCH₂CF₃ Br Br CF₃ CF₃ Cl Br CF₃ CF₃ Br Br CF₃ Cl Cl BrCF₃ Cl Br Br CF₃ Br Cl Br CF₃ Br Br Br CF₃ OCH₂CF₃ Cl Br CF₃ OCH₂CF₃ Br

[0223] As shown in Scheme 2 and further illustrated in Examples 1-10,the pyrazolecarboxylic acids of Formula 4 such as those listed in Table3 are useful in preparing the compounds of Formula 1, including thoselisted in Table 1. TABLE 3 4

R³ R⁵ CF₃ Cl Cl Cl Br Cl OCH₂CF₃ Cl CF₃ Br Cl Br Br Br OCH₂CF₃ Br

[0224] Formulation/Utility

[0225] Compounds of this invention will generally be used as aformulation or composition with an agriculturally suitable carriercomprising at least one of a liquid diluent, a solid diluent or asurfactant. The formulation or composition ingredients are selected tobe consistent with the physical properties of the active ingredient,mode of application and environmental factors such as soil type,moisture and temperature. Useful formulations include liquids such assolutions (including emulsifiable concentrates), suspensions, emulsions(including microemulsions and/or suspoemulsions) and the like whichoptionally can be thickened into gels. Useful formulations furtherinclude solids such as dusts, powders, granules, pellets, tablets,films, and the like which can be water-dispersible (“wettable”) orwater-soluble. Active ingredient can be (micro)encapsulated and furtherformed into a suspension or solid formulation; alternatively the entireformulation of active ingredient can be encapsulated (or “overcoated”).Encapsulation can control or delay release of the active ingredient.Sprayable formulations can be extended in suitable media and used atspray volumes from about one to several hundred liters per hectare.High-strength compositions are primarily used as intermediates forfurther formulation.

[0226] The formulations will typically contain effective amounts ofactive ingredient, diluent and surfactant within the followingapproximate ranges that add up to 100 percent by weight. Weight PercentActive Ingredient Diluent Surfactant Water-Dispersible and Water-  5-90 0-94  1-15 soluble Granules, Tablets and Powders. Suspensions,Emulsions, Solutions  5-50 40-95  0-15 (including EmulsifiableConcentrates) Dusts  1-25 70-99  0-5 Granules and Pellets 0.01-99     5-99.99  0-15 High Strength Compositions 90-99  0-10 0-2

[0227] Typical solid diluents are described in Watkins, et al., Handbookof Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books,Caldwell, N.J. Typical liquid diluents are described in Marsden,Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon'sDetergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, N.J.,as well as Sisely and Wood, Encyclopedia of Surface Active Agents,Chemical. Publ. Co., Inc., New York, 1964, list surfactants andrecommended uses. All formulations can contain minor amounts ofadditives to reduce foam, caking, corrosion, microbiological growth andthe like, or thickeners to increase viscosity.

[0228] Surfactants include, for example, polyethoxylated alcohols,polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acidesters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzenesulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates,naphthalene sulfonate formaldehyde condensates, polycarboxylates, andpolyoxyethylene/polyoxypropylene block copolymers. Solid diluentsinclude, for example, clays such as bentonite, montmorillonite,attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth,urea, calcium carbonate, sodium carbonate and bicarbonate, and sodiumsulfate. Liquid diluents include, for example, water,N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethyleneglycol, polypropylene glycol, propylene carbonate, dibasic esters,paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor,linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed andcoconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone,isophorone and 4-hydroxymethyl-2-pentanone, and alcohols such asmethanol, cyclohexanol, decanol, benzyl and tetrahydrofurfuryl alcohol.

[0229] Solutions, including emulsifiable concentrates, can be preparedby simply mixing the ingredients. Dusts and powders can be prepared byblending and, usually, grinding as in a hammer mill or fluid-energymill. Suspensions are usually prepared by wet-milling; see, for example,U.S. Pat. No. 3,060,084. Granules and pellets can be prepared byspraying the active material upon preformed granular carriers or byagglomeration techniques. See Browning, “Agglomeration”, ChemicalEngineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer'sHandbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 andfollowing, and PCT Publication WO 91/13546. Pellets can be prepared asdescribed in U.S. Pat. No. 4,172,714. Water-dispersible andwater-soluble granules can be prepared as taught in U.S. Pat. No.4,144,050, U.S. Pat. No. 3,920,442 and DE 3,246,493. Tablets can beprepared as taught in U.S. Pat. No. 5,180,587, U.S. Pat. No. 5,232,701and U.S. Pat. No. 5,208,030. Films can be prepared as taught in GB2,095,558 and U.S. Pat. No. 3,299,566.

[0230] For further information regarding the art of formulation, see T.S. Woods, “The Formulator's Toolbox—Product Forms for Modem Agriculture”in Pesticide Chemistry and Bioscience, The Food-Environment Challenge,T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th InternationalCongress on Pesticide Chemistry, The Royal Society of Chemistry,Cambridge, 1999, pp. 120-133. See also U.S. Pat. No. 3,235,361, Col. 6,line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12,15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182;U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 andExamples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons,Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook,8th Ed., Blackwell Scientific Publications, Oxford, 1989.

[0231] In the following Examples, all percentages are by weight and allformulations are prepared in conventional ways. Compound numbers referto compounds in Index Table A.

EXAMPLE A

[0232] Wettable Powder Compound 2 65.0% dodecylphenol polyethyleneglycol ether  2.0% sodium ligninsulfonate  4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.

EXAMPLE B

[0233] Granule Compound 10 10.0% attapulgite granules (low volatilematter, 90.0%. 0.71/0.30 mm; U.S.S. No. 25-50 sieves)

EXAMPLE C

[0234] Extruded Pellet Compound 20 25.0% anhydrous sodium sulfate 10.0%crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0%calcium/magnesium bentonite 59.0%.

EXAMPLE D

[0235] Emulsifiable Concentrate Compound 33 20.0% blend of oil solublesulfonates 10.0% and polyoxyethylene ethers isophorone 70.0%.

[0236] Compounds of this invention are characterized by favorablemetabolic and/or soil residual patterns and exhibit activity controllinga spectrum of agronomic and non-agronomic invertebrate pests. (In thecontext of this disclosure “invertebrate pest control” means inhibitionof invertebrate pest development (including mortality) that causessignificant reduction in feeding or other injury or damage caused by thepest; related expressions are defined analogously.) As referred to inthis disclosure, the term “invertebrate pest” includes arthropods,gastropods and nematodes of economic importance as pests. The term“arthropod” includes insects, mites, spiders, scorpions, centipedes,millipedes, pill bugs and symphylans. The term “gastropod” includessnails, slugs and other Stylommatophora. The term “nematode” includesall of the helminths, such as: roundworms, heartworms, and phytophagousnematodes (Nematoda), flukes (Tematoda), Acanthocephala, and tapeworms(Cestoda). Those skilled in the art will recognize that not allcompounds are equally effective against all pests. Compounds of thisinvention display activity against economically important agronomic andnonagronomic pests. The term “agronomic” refers to the production offield crops such as for food and fiber and includes the growth of cerealcrops (e.g., wheat, oats, barley, rye, rice, maize), soybeans, vegetablecrops (e.g., lettuce, cabbage, tomatoes, beans), potatoes, sweetpotatoes, grapes, cotton, and tree fruits (e.g., pome fruits, stonefruits and citrus fruits). The term “nonagronomic” refers to otherhorticultural (e.g., forest, greenhouse, nursery or ornamental plantsnot grown in a field), public (human), and animal health, domestic andcommercial structure, household, and stored product applications orpests. For reason of invertebrate pest control spectrum and economicimportance, protection (from damage or injury caused by invertebratepests) of agronomic crops of cotton, maize, soybeans, rice, vegetablecrops, potato, sweet potato, grapes and tree fruit by controllinginvertebrate pests are preferred embodiments of the invention. Agronomicor nonagronomic pests include larvae of the order Lepidoptera, such asarmyworms, cutworms, loopers, and heliothines in the family Noctuidae(e.g., fall armyworm (Spodoptera fugiperda J. E. Smith), beet armyworm(Spodoptera exigua Hübner), black cutworm (Agrotis ipsilon Hufnagel),cabbage looper (Trichoplusia ni Hübner), tobacco budworm (Heliothisvirescens Fabricius)); borers, casebearers, webworms, coneworms,cabbageworms and skeletonizers from the family Pyralidae (e.g., Europeancorn borer (Ostrinia nubilalis Hübner), navel orangeworm (Amyeloistransitella Walker), corn root webworm (Crambus caliginosellus Clemens),sod webworm (Herpetogramma licarsisalis Walker)); leafrollers, budworms,seed worms, and fruit worms in the family Tortricidae (e.g., codlingmoth (Cydia pomonella Linnaeus), grape berry moth (Endopiza viteanaClemens), oriental fruit moth (Grapholita molesta Busek)); and manyother economically important lepidoptera (e.g., diamondback moth(Plutella xylostella Linnaeus), pink bollworm (Pectinophora gossypiellaSaunders), gypsy moth (Lymantria dispar Linnaeus)); nymphs and adults ofthe order Blattodea including cockroaches from the families Blattellidaeand Blattidae (e.g., oriental cockroach (Blatta orientalis Linnaeus),Asian cockroach (Blatella asahinai Mizukubo), German cockroach(Blattella germanica Linnaeus), brownbanded cockroach (Supellalongipalpa Fabricius), American cockroach (Periplaneta americanaLinnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeiracockroach (Leucophaea maderae Fabricius)); foliar feeding larvae andadults of the order Coleoptera including weevils from the familiesAnthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomusgrandis Boheman), rice water weevil (Lissorhoptrus oryzophilus Kuschel),granary weevil (Sitophilus granarius Linnaeus), rice weevil (Sitophilusoryzae Linnaeus)); flea beetles, cucumber beetles, rootworms, leafbeetles, potato beetles, and leafminers in the family Chrysomelidae(e.g., Colorado potato beetle (Leptinotarsa decemlineata Say), westerncorn rootworm (Diabrotica virgifera virgifera LeConte)); chafers andother beetles from the family Scaribaeidae (e.g., Japanese beetle(Popillia japonica Newman) and European chafer (Rhizotrogus majalisRazoumowsky)); carpet beetles from the family Dermestidae; wirewormsfrom the family Elateridae; bark beetles from the family Scolytidae andflour beetles from the family Tenebrionidae. In addition, agronomic andnonagronomic pests include: adults and larvae of the order Dermapteraincluding earwigs from the family Forficulidae (e.g., European earwig(Forficula auricularia Linnaeus), black earwig (Chelisoches morioFabricius)); adults and nymphs of the orders Hemiptera and Homopterasuch as, plant bugs from the family Miridae, cicadas from the familyCicadidae, leafhoppers (e.g. Empoasca spp.) from the familyCicadellidae, planthoppers from the families Fulgoroidae andDelphacidae, treehoppers from the family Membracidae, psyllids from thefamily Psyllidae, whiteflies from the family Aleyrodidae, aphids fromthe family Aphididae, phylloxera from the family Phylloxeridae,mealybugs from the family Pseudococcidae, scales from the familiesCoccidae, Diaspididae and Margarodidae, lace bugs from the familyTingidae, stink bugs from the family Pentatomidae, cinch bugs (e.g.,Blissus spp.) and other seed bugs from the family Lygaeidae, spittlebugsfrom the family Cercopidae squash bugs from the family Coreidae, and redbugs and cotton stainers from the family Pyrrhocoridae. Also includedare adults and larvae of the order Acari (mites) such as spider mitesand red mites in the family Tetranychidae (e.g., European red mite(Panonychus ulmi Koch), two spotted spider mite (Tetranychus urticaeKoch), McDaniel mite (Tetranychus mcdanieli McGregor)), flat mites inthe family Tenuipalpidae (e.g., citrus flat mite (Brevipalpus lewisiMcGregor)), rust and bud mites in the family Eriophyidae and otherfoliar feeding mites and mites important in human and animal health,i.e. dust mites in the family Epidermoptidae, follicle mites in thefamily Demodicidae, grain mites in the family Glycyphagidae, ticks inthe order Ixodidae (e.g., deer tick (Ixodes scapularis Say), Australianparalysis tick (Ixodes holocyclus Neumann), American dog tick(Dermacentor variabilis Say), lone star tick (Amblyomma americanumLinnaeus) and scab and itch mites in the families Psoroptidae,Pyemotidae, and Sarcoptidae; adults and immatures of the orderOrthoptera including grasshoppers, locusts and crickets (e.g., migratorygrasshoppers (e.g., Melanoplus sanguinipes Fabricius, M. differentialisThomas), American grasshoppers (e.g., Schistocerca americana Drury),desert locust (Schistocerca gregaria Forskal), migratory locust (Locustamigratoria Linnaeus), house cricket (Acheta domesticus Linnaeus), molecrickets (Gryllotalpa spp.)); adults and immatures of the order Dipteraincluding leafminers, midges, fruit flies (Tephritidae), frit flies(e.g., Oscinella frit Linnaeus), soil maggots, house flies (e.g., Muscadomestica Linnaeus), lesser house flies (e.g., Fannia canicularisLinnaeus, F. femoralis Stein), stable flies (e.g., Stomoxys calcitransLinnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp.,Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanusspp.), bot flies (e.g., Gastrophilus spp., Oestrus spp.), cattle grubs(e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g.,Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g.,Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimuliumspp., Simulium spp.), biting midges, sand flies, sciarids, and otherNematocera; adults and immatures of the order Thysanoptera includingonion thrips (Thrips tabaci Lindeman) and other foliar feeding thrips;insect pests of the order Hymenoptera including ants (e.g., redcarpenter ant (Camponotus ferrugineus Fabricius), black carpenter ant(Camponotus pennsylvanicus De Geer), Pharaoh ant (Monomorium pharaonisLinnaeus), little fire ant (Wasmannia auropunctata Roger), fire ant(Solenopsis geminata Fabricius), red imported fire ant (Solenopsisinvicta Buren), Argentine ant (Iridomyrmex humilis Mayr), crazy ant(Paratrechina longicornis Latreille), pavement ant (Tetramoriumcaespitum Linnaeus), cornfield ant (Lasius alienus Förster), odoroushouse ant (Tapinoma sessile Say)), bees (including carpenter bees),hornets, yellow jackets and wasps; insect pests of the order Isopteraincluding the eastern subterranean termite (Reticulitermes flavipesKollar), western subterranean termite (Reticulitermes hesperus Banks),Formosan subterranean termite (Coptotermes formosanus Shiraki), WestIndian drywood termite (Incisitermes immigrans Snyder) and othertermites of economic importance; insect pests of the order Thysanurasuch as silverfish (Lepisma saccharina Linnaeus) and firebrat (Thermobiadomestica Packard); insect pests of the order Mallophaga and includingthe head louse (Pediculus humanus capitis De Geer), body louse(Pediculus humanus humanus Linnaeus), chicken body louse (Menacanthusstramineus Nitszch), dog biting louse (Trichodectes canis De Geer),fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicolaovis Schrank), short-nosed cattle louse (Haematopinus eurysternusNitzsch), long-nosed cattle louse (Linognathus vituli Linnaeus) andother sucking and chewing parasitic lice that attack man and animals;insect pests of the order Siphonoptera including the oriental rat flea(Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felisBouche), dog flea (Ctenocephalides canis Curtis), hen flea(Ceratophyllus gallinae Schrank), sticktight flea (Echidnophagagallinacea Westwood), human flea (Pulex irritans Linnaeus) and otherfleas afflicting mammals and birds. Additional arthropod pests coveredinclude: spiders in the order Araneae such as the brown recluse spider(Loxosceles reclusa Gertsch & Mulaik) and the black widow spider(Latrodectus mactans Fabricius), and centipedes in the orderScutigeromorpha such as the house centipede (Scutigera coleoptrataLinnaeus). Compounds of the present invention also have activity onmembers of the Classes Nematoda, Cestoda, Trematoda, and Acanthocephalaincluding economically important members of the orders Strongylida,Ascaridida, Oxyurida, Rhabditida, Spirurida, and Enoplida such as butnot limited to economically important agricultural pests (i.e. root knotnematodes in the genus Meloidogyne, lesion nematodes in the genusPratylenchus, stubby root nematodes in the genus Trichodorus, etc.) andanimal and human health pests (i.e. all economically important flukes,tapeworms, and roundworms, such as Strongylus vulgaris in horses,Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilariaimmitis Leidy in dogs, Anoplocephala perfoliata in horses, Fasciolahepatica Linnaeus in ruminants, etc.).

[0237] Compounds of the invention show particularly high activityagainst pests in the order Lepidoptera (e.g., Alabama argillacea Hübner(cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller),A. rosana Linnaeus (European leaf roller) and other Archips species,Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalisGuenee (rice leaf roller), Crambus caliginosellus Clemens (corn rootwebworm), Crambus teterrellus Zincken (bluegrass webworm), Cydiapomonella Linnaeus (codling moth), Earias insulana Boisduval (spinybollworm), Earias vittella Fabricius (spotted bollworm), Helicoverpaarmigera Hübner (American bollworm), Helicoverpa zea Boddie (cornearworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogrammalicarsisalis Walker (sod webworm), Lobesia botrana Denis &Schiffermüller (grape berry moth), Pectinophora gossypiella Saunders(pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer),Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus(small white butterfly), Plutella xylostella Linnaeus (diamondbackmoth), Spodoptera exigua Hübner (beet armyworm), Spodoptera lituraFabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperdaJ. E. Smith (fall armyworm), Trichoplusia ni Hübner (cabbage looper) andTuta absoluta Meyrick (tomato leafminer)). Compounds of the inventionalso have commercially significant activity on members from the orderHomoptera including: Acyrthisiphon pisum Harris (pea aphid), Aphiscraccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid),Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer(apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solaniKaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell(strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheataphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosomalanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy(mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid),Metopolophium dirrhodum Walker (cereal aphid), Macrosipum euphorbiaeThomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, greenpeach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigusspp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (cornleaf aphid), Rhopalosiphum padi Linnaeus (bird cherry-oat aphid),Schizaphis graminum Rondani (greenbug), Sitobion avenae Fabricius(English grain aphid), Therioaphis maculata Buckton (spotted alfalfaaphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid),and Toxoptera citricida Kirkaldy (brown citrus aphid); Adelges spp.(adelgids); Phylloxera devastatrix Pergande (pecan phylloxera); Bemisiatabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisiaargentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes citriAshmead (citrus whitefly) and Trialeurodes vaporariorum Westwood(greenhouse whitefly); Empoasca fabae Harris (potato leafhopper),Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestesquadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler(green leafhopper), Nephotettix nigropictus Stål (rice leafhopper),Nilaparvata lugens Stål (brown planthopper), Peregrinus maidis Ashmead(corn planthopper), Sogatella furcifera Horvath (white-backedplanthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocybapomaria McAtee white apple leafhopper, Erythroneoura spp. (grapeleafhoppers); Magicidada septendecim Linnaeus (periodical cicada);Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotusperniciosus Comstock (San Jose scale); Planococcus citri Risso (citrusmealybug); Pseudococcus spp. (other mealybug complex); Cacopsyllapyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmonpsylla). These compounds also have activity on members from the orderHemiptera including: Acrosternum hilare Say (green stink bug), Anasatristis De Geer (squash bug), Blissus leucopterus leucopterus Say(chinch bug), Corythuca gossypii Fabricius (cotton lace bug),Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellusHerrich-Schäffer (cotton stainer), Euchistus servus Say (brown stinkbug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug),Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say(leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois(tarnished plant bug), Nezara viridula Linnaeus (southern green stinkbug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatusDallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cottonfleahopper). Other insect orders controlled by compounds of theinvention include Thysanoptera (e.g., Frankliniella occidentalisPergande (western flower thrip), Scirthothrips citri Moulton (citrusthrip), Sericothrips variabilis Beach (soybean thrip), and Thrips tabaciLindeman (onion thrip); and the order Coleoptera (e.g., Leptinotarsadecemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant(Mexican bean beetle) and wireworms of the genera Agriotes, Athous orLimonius).

[0238] Compounds of this invention can also be mixed with one or moreother biologically active compounds or agents including insecticides,fungicides, nematocides, bactericides, acaricides, growth regulatorssuch as rooting stimulants, chemosterilants, semiochemicals, repellents,attractants, pheromones, feeding stimulants, other biologically activecompounds or entomopathogenic bacteria, virus or fungi to form amulti-component pesticide giving an even broader spectrum ofagricultural utility. Thus the present invention also pertains to acomposition comprising a biologically effective amount of a compound ofFormula 1 and an effective amount of at least one additionalbiologically active compound or agent and can further comprise at leastone of a surfactant, a solid diluent or a liquid diluent. Examples ofsuch biologically active compounds or agents with which compounds ofthis invention can be formulated are: insecticides such as abamectin,acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin,azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran,chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl,chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin,lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin,diafenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan,emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb,fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid,flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron,fonophos, halofenozide, hexaflumuron, imidacloprid, indoxacarb,isofenphos, lufenuron, malathion, metaldehyde, methamidophos,methidathion, methomyl, methoprene, methoxychlor, monocrotophos,methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl,parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet,phosphamidon, pirimicarb, profenofos, pymetrozine, pyridalyl,pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos,tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos,thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin,trichlorfon and triflumuron; fungicides such as acibenzolar,azoxystrobin, benomyl, blasticidin-S, Bordeaux mixture (tribasic coppersulfate), bromuconazole, carpropamid, captafol, captan, carbendazim,chloroneb, chlorothalonil, copper oxychloride, copper salts,cyflufenamid, cymoxanil, cyproconazole, cyprodinil,(S)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one(RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin,fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil,flumetover (RPA 403397), flumorf/flumorlin (SYP-L190), fluoxastrobin(HEC 5725), fluquinconazole, flusilazole, flutolanil, flutriafol,folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658),hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane,kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil,metalaxyl, metconazole, metominostrobin/fenominostrobin (SSF-126),metrafenone (AC375839), myclobutanil, neo-asozin (ferricmethanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl,penconazole, pencycuron, probenazole, prochloraz, propamocarb,propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU 6476),pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen,spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon,triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycinand vinclozolin; nematocides such as aldicarb, oxamyl and fenamiphos;bactericides such as streptomycin; acaricides such as amitraz,chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor,etoxazole, fenazaquin, fenbutatin oxide, fenpropatbrin, fenpyroximate,hexythiazox, propargite, pyridaben and tebufenpyrad; and biologicalagents such as Bacillus thuringiensis including ssp. aizawai andkurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, andentomopathogenic bacteria, virus and fungi. Compounds of this inventionand compositions thereof can be applied to plants geneticallytransformed to express proteins toxic to invertebrate pests (such asBacillus thuringiensis toxin). The effect of the exogenously appliedinvertebrate pest control compounds of this invention may be synergisticwith the expressed toxin proteins.

[0239] A general reference for these agricultural protectants is ThePesticide Manual, 12th Edition, C. D. S. Tomlin, Ed., British CropProtection Council, Farnham, Surrey, U.K., 2000.

[0240] Preferred insecticides and acaricides for mixing with compoundsof this invention include pyrethroids such as cypermethrin, cyhalothrin,cyfluthrin, beta-cyfluthrin, esfenvalerate, fenvalerate andtralomethrin; carbamates such as fenothicarb, methomyl, oxamyl andthiodicarb; neonicotinoids such as clothianidin, imidacloprid andthiacloprid; neuronal sodium channel blockers such as indoxacarb;insecticidal macrocyclic lactones such as spinosad, abamectin,avermectin and emamectin; γ-aminobutyric acid (GABA) antagonists such asendosulfan, ethiprole and fipronil; insecticidal ureas such asflufenoxuron and triflumuron; juvenile hormone mimics such as diofenolanand pyriproxyfen; pymetrozine; and amitraz. Preferred biological agentsfor mixing with compounds of this invention include Bacillusthuringiensis and Bacillus thuringiensis delta endotoxin as well asnaturally occurring and genetically modified viral insecticidesincluding members of the family Baculoviridae as well as entomophagousfungi.

[0241] Most preferred mixtures include a mixture of a compound of thisinvention with cyhalothrin; a mixture of a compound of this inventionwith beta-cyfluthrin; a mixture of a compound of this invention withesfenvalerate; a mixture of a compound of this invention with methomyl;a mixture of a compound of this invention with imidacloprid; a mixtureof a compound of this invention with thiacloprid; a mixture of acompound of this invention with indoxacarb; a mixture of a compound ofthis invention with abamectin; a mixture of a compound of this inventionwith endosulfan; a mixture of a compound of this invention withethiprole; a mixture of a compound of this invention with fipronil; amixture of a compound of this invention with flufenoxuron; a mixture ofa compound of this invention with pyriproxyfen; a mixture of a compoundof this invention with pymetrozine; a mixture of a compound of thisinvention with amitraz; a mixture of a compound of this invention withBacillus thuringiensis and a mixture of a compound of this inventionwith Bacillus thuringiensis delta endotoxin.

[0242] In certain instances, combinations with other invertebrate pestcontrol compounds or agents having a similar spectrum of control but adifferent mode of action will be particularly advantageous forresistance management. Thus, compositions of the present invention canfurther comprise a biologically effective amount of at least oneadditional invertebrate pest control compound or agent having a similarspectrum of control but a different mode of action. Contacting a plantgenetically modified to express a plant protection compound (e.g.,protein) or the locus of the plant with a biologically effective amountof a compound of invention can also provide a broader spectrum of plantprotection and be advantageous for resistance management.

[0243] Invertebrate pests are controlled in agronomic and nonagronomicapplications by applying one or more of the compounds of this invention,in an effective amount, to the environment of the pests including theagronomic and/or nonagronomic locus of infestation, to the area to beprotected, or directly on the pests to be controlled. Thus, the presentinvention further comprises a method for controlling an invertebratepest, comprising contacting the invertebrate pest or its environmentwith a biologically effective amount of one or more of the compounds ofthe invention, or with a composition comprising at least one suchcompound, or with a composition comprising at least one such compoundand an effective amount of at least one additional biologically activecompound or agent. Examples of suitable compositions comprising acompound of the invention and an effective amount of at least oneadditional biologically active compound or agent include granularcompositions wherein the additional biologically active compound oragent is present on the same granule as the compound of the invention oron granules separate from those of the compound of this invention.

[0244] A preferred method of contact is by spraying. Alternatively, agranular composition comprising a compound of the invention can beapplied to the plant foliage or the soil. Compounds of this inventionare also effectively delivered through plant uptake by contacting theplant with a composition comprising a compound of this invention appliedas a soil drench of a liquid formulation, a granular formulation to thesoil, a nursery box treatment or a dip of transplants. Compounds arealso effective by topical application of a composition comprising acompound of this invention to the locus of infestation. Other methods ofcontact include application of a compound or a composition of theinvention by direct and residual sprays, aerial sprays, gels, seedcoatings, microencapsulations, systemic uptake, baits, eartags, boluses,foggers, fumigants, aerosols, dusts and many others. The compounds ofthis invention may also be impregnated into materials for fabricatinginvertebrate control devices (e.g., insect netting).

[0245] The compounds of this invention can be incorporated into baitsthat are consumed by the invertebrates or within devices such as trapsand the like. Granules or baits comprising between 0.01-5% activeingredient, 0.0510% moisture retaining agent(s) and 40-99% vegetableflour are effective in controlling soil insects at very low applicationrates, particularly at doses of active ingredient that are lethal byingestion rather than by direct contact.

[0246] The compounds of this invention can be applied in their purestate, but most often application will be of a formulation comprisingone or more compounds with suitable carriers, diluents, and surfactantsand possibly in combination with a food depending on the contemplatedend use. A preferred method of application involves spraying a waterdispersion or refined oil solution of the compounds. Combinations withspray oils, spray oil concentrations, spreader stickers, adjuvants,other solvents, and synergists such as piperonyl butoxide often enhancecompound efficacy.

[0247] The rate of application required for effective control (i.e.“biologically effective amount”) will depend on such factors as thespecies of invertebrate to be controlled, the pest's life cycle, lifestage, its size, location, time of year, host crop or animal, feedingbehavior, mating behavior, ambient moisture, temperature, and the like.Under normal circumstances, application rates of about 0.01 to 2 kg ofactive ingredient per hectare are sufficient to control pests inagronomic ecosystems, but as little as 0.0001 kg/hectare may besufficient or as much as 8 kg/hectare may be required. For nonagronomicapplications, effective use rates will range from about 1.0 to 50mg/square meter but as little as 0.1 mg/square meter may be sufficientor as much as 150 mg/square meter may be required. One skilled in theart can easily determine the biologically effective amount necessary forthe desired level of invertebrate pest control.

[0248] The following Tests in the Biological Examples of the Inventiondemonstrate the control efficacy of compounds of this invention onspecific pests. “Control efficacy” represents inhibition of arthropoddevelopment (including mortality) that causes significantly reducedfeeding. The pest control protection afforded by the compounds is notlimited, however, to these species. See Index Table A for compounddescriptions. The following abbreviations are used in the Index Tablewhich follows: t is tertiary, n is normal, i is iso, s is secondary, Meis methyl, Et is ethyl, Pr is propyl and Bu is butyl; accordingly i-Pris isopropyl, s-Bu is secondary butyl, etc. The abbreviation “Ex.”stands for “Example” and is followed by a number indicating in whichexample the compound is prepared. INDEX TABLE A

Compound R¹ R² R³ R^(4a) R^(4b) R⁵ m.p. (° C.)  1 Me Br CF₃ i-Pr H Cl197-198  2 (Ex. 1) Me Cl CF₃ i-Pr H Cl 195-196  3 Me Cl CF₃ t-Bu H Cl223-225  4 (Ex. 2) Me Cl CF₃ Me H Cl 185-186  5 Br Br CF₃ i-Pr H Cl192-193  6 Br Br CF₃ t-Bu H Cl 246-247  7 Br Br CF₃ Me H Cl 162-163  8Br Br CF₃ Et H Cl 188-189  9 Cl Cl CF₃ i-Pr H Cl 200-201  10 Cl Cl CF₃t-Bu H Cl 170-172  11 Cl Cl CF₃ Me H Cl 155-157  12 Cl Cl CF₃ Et H Cl201-202  13 Me Br CF₃ t-Bu H Cl 247-248  14 Me Br CF₃ Et H Cl 192-193 15 Me F CF₃ i-Pr H Cl 179-180  16 Me Br Br i-Pr H Cl 185-187  17 Me CF₃CF₃ i-Pr H Cl 235-236  18 Me CF₃ CF₃ Et H Cl 216-217  19 Me I CF₃ i-Pr HCl 188-189  20 (Ex. 6) Me Cl Br Me H Cl 162-164  21 Me Cl Br t-Bu H Cl159-161  22 Br Br Br i-Pr H Cl 162-163  23 Br Br Br Me H Cl 166-168  24Br Br Br t-Bu H Cl 210-212  25 Cl Cl Br i-Pr H Cl 188-190  26 Cl Cl Brt-Bu H Cl 179-180  27 (Ex. 5) Me Cl Br i-Pr H Cl 159-161  28 Cl Cl CF₃i-Pr H Cl 200-202  29 Cl Br CF₃ t-Bu H Cl 143-145  30 Cl Br CF₃ Me H Cl171-173  31 Me Br Br Me H Cl 147-149  32 Me Br CF₃ Me H Cl 222-223  33(Ex. 3) Me Cl Cl i-Pr H Cl 173-175  34 (Ex. 4) Me Cl Cl Me H Cl 225-226 35 Me Cl Cl t-Bu H Cl 163-165  36 Me Br Cl i-Pr H Cl 152-153  37 Me BrCl Me H Cl 140-141  38 Me Br Br t-Bu H Cl 215-221  39 Me I CF₃ Me H Cl199-200  40 Me CF₃ CF₃ t-Bu H Cl 148-149  41 Me Cl Cl Et H Cl 199-200 42 Br Br Cl i-Pr H Cl 197-199  43 Br Br Cl Me H Cl 188-190  44 Br Br Clt-Bu H Cl 194-196  45 Br Br Cl Et H Cl 192-194  46 Cl Cl Cl i-Pr H Cl197-199  47 Cl Cl Cl Me H Cl 205-206  48 Cl Cl Cl t-Bu H Cl 172-173  49Cl Cl Cl Et H Cl 206-208  50 Me F Br t-Bu H Cl 124-125  51 Br Br Br Et HCl 196-197  52 Cl Cl Br Me H Cl 245-246  53 Cl Cl Br Et H Cl 214-215  54Me Br Br Et H Cl 194-196  55 Me I Br Me H Cl 229-230  56 Me I Br i-Pr HCl 191-192  57 Me CF₃ CF₃ Me H Cl 249-250  58 Me Cl CF₃ Et H Cl 163-164 59 Me I CF₃ Et H Cl 199-200  60 Me I CF₃ t-Bu H Cl 242-243  61 Me Cl BrEt H Cl 194-195  62 Me F CF₃ Me H Cl 213-214  63 Me F CF₃ Et H Cl212-213  64 Me F CF₃ t-Bu H Cl 142-143  65 Me F Br Me H Cl 214-215  66Me F Br Et H Cl 205-205  67 Me F Br i-Pr H Cl 206-208  68 Me F Cl i-Pr HCl 184-185  69 Me F Cl Me H Cl 180-182  70 Me F Cl Et H Cl 163-165  71Me Br Cl Et H Cl 192-194  72 Me I Cl Me H Cl 233-234  73 Me I Cl Et H Cl196-197  74 Me I Cl i-Pr H Cl 189-190  75 Me I Cl t-Bu H Cl 228-229  76Me Br Cl t-Bu H Cl 224-225  77 Br Br Cl Me Me Cl 153-155  78 Me Br CF₃Me Me Cl 207-208  79 Cl Cl Cl Me Me Cl 231-232  80 Br Br Br Me Me Cl189-190  81 Cl Cl Br Me Me Cl 216-218  82 Cl Cl CF₃ Me Me Cl 225-227  83Me Br OCH₂CF₃ i-Pr H Cl 213-215  84 Me Br OCH₂CF₃ Me H Cl 206-208  85 MeCl OCH₂CF₃ i-Pr H Cl 217-218  86 Me Cl OCH₂CF₃ Et H Cl 205-207  87 (Ex.10) Me Cl OCH₂CF₃ Me H Cl 207-208  88 Me Br OCH₂CF₃ Et H Cl 208-211  89Me Br OCH₂CF₃ t-Bu H Cl 213-216  90 Br Br CF₃ Me Me Cl 228-229  91 Cl BrCF₃ Me Me Cl 238-239  92 Cl C OCH₂CF₃ i-Pr H Cl 232-235  93 Cl ClOCH₂CF₃ Me H Cl 192-195  94 Cl Cl OCH₂CF₃ Me Me Cl 132-135  95 Br BrOCH₂CF₃ i-Pr H Cl 225-227  96 Br Br OCH₂CF₃ Me H Cl 206-208  97 Br BrOCH₂CF₃ Me Me Cl 175-177  98 Cl Br Br Me Me Cl 237-238  99 Cl Br Cl Me HCl 228-229 100 Cl Br Cl Me Me Cl 236-237 101 Cl Br Br Me H Cl 226-227102 Cl F CF₃ Me Me Cl 215-216 103 Cl F CF₃ Me H Cl 219-220 104 Br F BrMe Me Cl 235-236 105 Br F Br Me H Cl 238-239 106 Br F Br i-Pr H Cl236-237 107 Br F Cl Me Me Cl 246-247 108 Br F Cl Me H Cl 233-234 109 BrF Cl i-Pr H Cl 153-154 110 Me F Cl Me Me Cl 242-243 111 Cl F Br Me Me Cl245-246 112 Cl F Br Me H Cl 217-218 113 Cl F Br i-Pr H Cl 168-169 114 ClF Cl Me Me Cl 239-240 115 Cl F Cl Me H Cl 248-249 116 Cl F Cl i-Pr H Cl169-170 117 Br F CF₃ Me Me Cl 191-192 118 Br F CF₃ Me H Cl 228-229 119Br F CF₃ i-Pr H Cl 224-226 120 Br Cl Br Me Me Cl 188-189 121 Br Cl Br MeH Cl 248-249 122 Br Cl Br i-Pr H Cl 252-253 123 Br Cl Cl Me Me Cl147-148 124 Br Cl Cl Me H Cl 249-250 125 Br Cl Cl i-Pr H Cl 239-240 126Br Cl CF₃ Me Me Cl 200-201 127 Br Cl CF₃ Me H Cl 158-159 128 Br Cl CF₃i-Pr H Cl 250-250 129 Me Cl Cl Me Me Cl 232-233 130 Me Cl Br Me Me Cl210-211 131 F F Br Me H Cl 197-198 132 F F Br Me Me Cl 218-222 133 F ClBr Me H Cl 203-204 134 F Cl Br Me Me Cl 226-227 135 F Cl Br i-Pr H Cl207-208 136 F Cl Cl Me H Cl 211-212 137 F Cl Cl Me Me Cl 237-238 138 F FCl Me H Cl 159-160 139 F F Cl Me Me Cl 225-226 140 F F Cl i-Pr H Cl201-202 141 F Br Br Me H Cl 209-210 142 F Br Br Me Me Cl 225-226 143 FBr Br i-Pr H Cl 208-209 144 F Br Cl Me H Cl 209-210 145 F Br Cl Me Me Cl244-245 146 F Br Cl i-Pr H Cl 207-208 147 F Br OCH₂CF₃ Me H Cl 210-211148 F Br OCH₂CF₃ Me Me Cl 204-206

BIOLOGICAL EXAMPLES OF THE INVENTION Test A

[0249] For evaluating control of diamondback moth (Plutella xylostella)the test unit consisted of a small open container with a 12-14-day-oldradish plant inside. This was pre-infested with 10-15 neonate larvae ona piece of insect diet by use of a core sampler to remove a plug from asheet of hardened insect diet having many larvae growing on it andtransfer the plug containing larvae and diet to the test unit. Thelarvae moved onto the test plant as the diet plug dried out.

[0250] Test compounds were formulated using a solution containing 10%acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc.), unless otherwiseindicated. The formulated compounds were applied in 1 mL of liquidthrough a SUJ2 atomizer nozzle with ⅛ JJ custom body (Spraying SystemsCo.) positioned 1.27 cm (0.5 inches) above the top of each test unit.All experimental compounds in this screen were sprayed at 50 ppm andreplicated three times. After spraying of the formulated test compound,each test unit was allowed to dry for 1 hour and then a black, screenedcap was placed on top. The test units were held for 6 days in a growthchamber at 25° C. and 70% reletive humidity. Plant feeding damage wasthen visually assessed.

[0251] Of the compounds tested, the following provided excellent levelsof plant protection (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127,128, 129, 130, 131, 132, 133, 134, 135, 136, 137.

Test B

[0252] For evaluating control of fall armyworm (Spodoptera frugiperda)the test unit consisted of a small open container with a 4-5-day-oldcorn (maize) plant inside. This was pre-infested with 10-15 1-day-oldlarvae on a piece of insect diet by use of a core sampler as describedfor Test A.

[0253] Test compounds were formulated and sprayed at 50 ppm as describedfor Test A. The applications were replicated three times. Afterspraying, the test units were maintained in a growth chamber and thenvisually rated as described for Test A.

[0254] Of the compounds tested, the following provided excellent levelsof plant protection (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127,128, 129, 130, 131, 132, 133, 134, 135, 136, 137.

Test C

[0255] For evaluating control of tobacco budworm (Heliothis virescens)the test unit consisted of a small open container with a 6-7 day oldcotton plant inside. This was pre-infested with 8 2-day-old larvae on apiece of insect diet by use of a core sampler as described for Test A.

[0256] Test compounds were formulated and sprayed at 50 ppm as describedfor Test A. The applications were replicated three times. Afterspraying, the test units were maintained in a growth chamber and thenvisually rated as described for Test A.

[0257] Of the compounds tested, the following provided excellent levelsof plant protection (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127,128, 129.

Test D

[0258] For evaluating control of beet armyworm (Spodoptera exigua) thetest unit consisted of a small open container with a 4-5-day-old cornplant inside. This was pre-infested with 10-15 1 -day-old larvae on apiece of insect diet by use of a core sampler as described for Test A.

[0259] Test compounds were formulated and sprayed at 50 ppm as describedfor Test A. The applications were replicated three times. Afterspraying, the test units were maintained in a growth chamber and thenvisually rated as described for Test A.

[0260] Of the compounds tested, the following provided excellent levelsof plant protection (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,100 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128,129.

Test E

[0261] For evaluating control of green peach aphid (Myzus persicae)through contact and/or systemic means, the test unit consisted of asmall open container with a 12-15-day-old radish plant inside. This waspre-infested by placing on a leaf of the test plant 30-40 insects on apiece of leaf excised from a culture plant (cut-leaf method). The larvaemoved onto the test plant as the leaf piece desiccated. Afterpre-infestation, the soil of the test unit was covered with a layer ofsand.

[0262] Test compounds were formulated using a solution containing 10%acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc.), unless otherwiseindicated. The formulated compounds were applied in 1 mL of liquidthrough a SUJ2 atomizer nozzle with ⅛ JJ custom body (Spraying SystemsCo.) positioned 1.27 cm (0.5 inches) above the top of each test unit.All experimental compounds in this screen were sprayed at 250 ppm andreplicated three times. After spraying of the formulated test compound,each test unit was allowed to dry for 1 hour and then a black, screenedcap was placed on top. The test units were held for 6 days in a growthchamber at 19-21° C. and 50-70% relative humidity. Each test unit wasthen visually assessed for insect mortality.

[0263] Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 20, 21, 22,23, 25, 26, 27, 28, 29, 31, 32, 33, 36, 38, 39, 41, 42, 43, 45, 46, 47,49, 51, 52, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 72,74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 93, 98, 99,100, 101, 102, 103, 104, 105, 106, 108, 109, 111, 112, 113, 114, 115,116, 126, 127, 128, 131, 135.

Test F

[0264] For evaluating control of cotton melon aphid (Aphis gossypii)through contact and/or systemic means, the test unit consisted of asmall open container with a 6-7-day-old cotton plant inside. This waspre-infested with 30-40 insects on a piece of leaf according to thecut-leaf method described for Test E, and the soil of the test unit wascovered with a layer of sand.

[0265] Test compounds were formulated and sprayed at 250 ppm asdescribed for Test E. The applications were replicated three times.After spraying, the test units were maintained in a growth chamber andthen visually rated as described for Test E.

[0266] Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 4, 5, 7, 8, 10, 11, 12, 13, 14, 16, 20, 21, 22, 23, 25,26, 27, 28, 29, 31, 32, 33, 34, 36, 38, 39, 42, 43, 45, 46, 47, 49, 51,52, 53, 54, 55, 56, 58, 59, 62, 63, 65, 66, 67, 77, 78, 79, 80, 81, 82,87, 88, 90, 91, 93, 94, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 119, 120, 121, 122,123, 124, 125, 126, 127, 128, 131, 133, 135, 136.

Test G

[0267] For evaluating control of silverleaf whitefly (Bemisia tabaci),the test unit consisted of a 14-21-day-old cotton plant grown inRedi-earth® media (Scotts Co.) with at least two true leaves infestedwith 2nd and 3rd instar nymphs on the underside of the leaves.

[0268] Test compounds were formulated in no more than 2 mL of acetoneand then diluted with water to 25-30 mL. The formulated compounds wereapplied using a flat fan air-assisted nozzle (Spraying Systems 122440)at 10 psi (69 kPa). Plants were sprayed to run-off on a turntablesprayer (patent application EP-1110617-A1). All experimental compoundsin this screen were sprayed at 250 ppm and replicated three times. Afterspraying of the test compound, the test units were held for 6 days in agrowth chamber at 50-60% relative humidity and 28° C. daytime and 24° C.nighttime temperature. Then the leaves were removed and then dead andlive nymphs were counted to calculate percent mortality.

[0269] Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 19, 20,21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 39, 42, 43, 45, 46, 47,49, 51, 52, 53, 54, 55, 56, 59, 77, 78, 79, 80, 81, 82, 87, 90, 93.

Test H

[0270] For evaluating soil systemic control of tobacco budworm(Heliothis virescens), cotton plants were grown in sassafras soil in15-cm pots in aluminum trays. When the plants reached square stage (budformation on the plant) the plants were treated with the test compounds.

[0271] Test compounds were formulated in 0.25 mL of acetone and thendiluted with water to provide solutions of 1, 5, 10 and 50 ppm. 10 mL ofthe treatment solutions were added to the pots weekly for four weeks,with four replicates of each treatment rate. One day after the second,third and fourth treatments, 35-50 first instar Heliothis virescenslarvae were brushed on each plant with paintbrushes and placed on theterminal area, squares, and bolls. Five days after the last infestationwith larvae the plants were rated for damage. Of the compounds tested,the following provided excellent levels of plant protection at 10 ppm(10% or less feeding damage): 16.

[0272] Of the compounds tested, the following also provided excellentprotection of squares and bolls at 10 ppm, with no feeding or minimalsepal damage: 16.

Test I

[0273] Test I followed an alternative protocol for evaluating soilsystemic control of tobacco budworm (Heliothis virescens). Cotton plantswere grown in sassafras soil in 15-cm pots under greenhouse conditions.When the plants reached square stage (bud formation on the plant) thesoil surface was treated with the test compounds.

[0274] Test compounds were formulated in 0.25 mL of acetone and thendiluted with water. Ten mL of treatment solution containing 3 mg ofcompound was added to the soil surface of each pot. The plants werewatered the next day and each day following as needed. At 1, 2 and 4days after treatment, leaves were excised for evaluation. Two sets ofleaves were selected from each plant: upper leaves at approximatelysecond node from terminal and with area greater than 25 cm² and lowerleaves at approximately third node from bottom and with area greaterthan 25 cm². The excised leaves were cut into 3 cm×2 cm sections andplaced into test trays made of high-impact styrene consisting of sixteencontiguous wells, each 6 cm wide, 4 cm long and 3 cm deep, with a clearplastic lid molded so that it locked into each well by friction.Solidified agar was placed into the bottom of each well to maintainmoisture for plant material. One second instar tobacco budworm wasplaced into each well with plant material; cells were sealed and held at25° C. and provided with 16 hours of light per day. For leaves excisedat 1, 2, and 4 days mortality was observed 4 days after treatment withone second instar todacco budworm.

[0275] Of the compounds tested, the following compounds providedexcellent levels of mortality (greater than 70% mortality) on upperleaves excised at 4 days after treatment at the test rate: 2, 27, 33.

Test J

[0276] For evaluating soil systemic control of fall armyworm (Spodopterafrugiperda), corn (maize) plants (Pioneer #3394) were grown in smallpots for 5 days until they were at least 4 cm tall and the first leafwas unfurling.

[0277] Test compounds were dissolved in 0.25 mL of acetone and dilutedwith water to provide solutions of 1, 10, 50 and 200 ppm. 1 mL of thetest solution was applied by pipette to the surface of the soil in eachpot, with eight plants for each compound/rate. The pots were covered andheld at 25° C. with 16 hours of light per day. The plants were wateredthe next day and each day following as needed. After 6 days, the plantmatter above the first leaf was excised and cut into 3-cm lengths. Eachtest unit was a high-impact styrene tray (Supplier: Clearpack Company,11610 Copenhagen Court, Franklin Park, Ill. 60131) consisting of sixteencontiguous wells each 6 cm wide, 4 cm long and 3 cm deep, with a clearplastic lid molded so that it locked into each well by friction.Solidified agar (2 to 4 mL) was placed onto the bottom of each well tomaintain moisture in the wells during the test. Each 3-cm length of cornplant matter was placed into a tray such that the plant matter wascontained within two wells. One second-instar fall armyworm (Spodopterafrugiperda) larva was placed in each well, the tray was covered and thenthe test units were held at 25° C. with 16 hours of light per day.Mortality was observed after four days.

[0278] LC₉₀ concentrations (test compound concentrations giving 90% killof the larvae) were calculated based on probit analysis dog linearregression) using a general linearized model (GLIM) of the SASstatistical computer analysis product of SAS Institute (Cary, N.C.,U.S.A.). Of the compounds tested, the following provided excellentlevels of mortality, with LC₉₀ values of 10 ppm or less: 1, 2, 4, 9, 11,12, 14, 16, 20, 22, 24, 31, 32, 33, 34.

Test K

[0279] For evaluating control of Colorado potato beetle (Leptinotarsadecemlineate), 5 mg samples of the test compounds were dissolved in 1 mLof acetone. This solution was then diluted to 100 mL total volume usingan aqueous 500 ppm solution of Ortho X-77™ surfactant. Serial dilutionswere made to obtain 50 mL of 10 ppm concentration.

[0280] The diluted solutions of the test compounds were sprayed torun-off on three-week-old potato or tomato plants. The plants wereplaced on a rotating turntable sprayer (10 rpm). Test solutions wereapplied using a flat fan air-assisted nozzle (Spraying Systems 122440)at 10 psi (69 kPa). After each treated plant had dried, leaves wereexcised from the treated plant. The leaves were cut into pieces, whichwere placed singly into 5.5 cm-by-3.5 cm cells of a sixteen-cell plastictray. Each cell contained a 2.5-cm square of moistened chromatographypaper to prevent desiccation. One second instar larvae was placed ineach cell. At three days after infestation the total number of deadColorado potato beetles was recorded.

[0281] Of the compounds tested, the following resulted in at least 90%mortality at 10 ppm: 2, 4, 27, 33, 34, 41, 61, 85.

Test L

[0282] For evaluating control of boll weevil (Anthonomus g. grandis),samples of the test compounds were dissolved in 1 mL of acetone. Thissolution was then diluted to 100 mL total volume using an aqueous 500ppm solution of Ortho X-77™ surfactant Serial dilutions were made toobtain 50 mL of 50 ppm concentration.

[0283] The diluted solutions of the test compounds were sprayed torun-off on three-week-old cotton plants. The plants were placed on arotating turntable sprayer (10 rpm). Test solutions were applied using aflat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69kPa). Sprayed and dried plants were incased in a plastic cylinder.Twenty weevils were placed in each cylinder containing a whole cottonplant. At three days after infestation a feeding damage rating wastaken.

[0284] Of the compounds tested, the following provided excellent levelsof plant protection at 50 ppm (10% or less feeding damage): 20, 27.

Test M

[0285] For evaluating control of thrips (Frankliniella sp.), samples ofthe test compounds were dissolved in 1 mL of acetone. This solution wasthen diluted to 100 mL total volume using an aqueous 500 ppm solution ofOrtho X-77™ surfactant. Serial dilutions were made to obtain 50 mL of 10ppm concentration.

[0286] The diluted solutions of the test compounds were sprayed torun-off on three-week-old cotton or soybean plants infested with thrips.The plants were placed on a rotating turntable sprayer (10 rpm). Testsolutions were applied using a flat fan air-assisted nozzle (SprayingSystems 122440) at 10 psi (69 kPa). Sprayed and dried plants wereincased in a plastic cylinder. At four days after application the totalnumber of dead thrips was recorded.

[0287] Of the compounds tested, the following resulted in at least 90%mortality at 10 ppm: 32.

What is claimed is:
 1. A compound selected from Formula 1 or an N-oxidethereof

wherein R¹ is CH₃, F, Cl or Br; R² is F, Cl, Br, I or CF₃; R³ is CF₃,Cl, Br or OCH₂CF₃; R^(4a) is C₁-C₄ alkyl; R^(4b) is H or CH₃; and R⁵ isCl or Br; or an agriculturally suitable salt thereof.
 2. A compound ofclaim 1 wherein R^(4a) is C₁-C₄ alkyl and R^(4b) is H; or R^(4a) is CH₃and R^(4b) is CH₃.
 3. A compound of claim 2 wherein R⁵ is Cl.
 4. Acompound of claim 3 wherein R^(4a) is CH₃, CH₂CH₃, CH(CH₃)₂ or C(CH₃)₃.5. A compound of claim 4 wherein R² is Cl or Br.
 6. A compound of claim5 wherein R¹ is CH₃.
 7. A compound of claim 5 wherein R¹ is Cl.
 8. Acompound of claim 1 that is selected from the group: the compound ofFormula 1 wherein R¹ is CH₃, R² is Br, R³ is CF₃, R^(4a) is CH(CH₃)₂,R^(4b) is H, and R⁵ is Cl; the compound of Formula 1 wherein R¹ is CH₃,R² is Br, R³ is CF₃, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl; thecompound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Br, R^(4a) isCH(CH₃)₂, R^(4b) is H, and R⁵ is Cl; the compound of Formula 1 whereinR¹ is CH₃, R² is Br, R³ is Br, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl;the compound of Formula 1 wherein R¹ is CH₃, R² is Br, R³ is Cl, R^(4a)is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl; the compound of Formula 1wherein R¹ is CH₃, R² is Br, R³ is Cl, R^(4a) is CH₃, R^(4b) is H, andR⁵ is Cl; the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ isCF₃, R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl; the compound ofFormula 1 wherein R¹ is CH₃, R² is Cl, R³ is CF₃, R^(4a) is CH₃, R^(4b)is H, and R⁵ is Cl; the compound of Formula 1 wherein R¹ is CH₃, R² isCl, R³ is Br, R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl; thecompound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Br, R^(4a) isCH₃, R^(4b) is H, and R⁵ is Cl; the compound of Formula 1 wherein R¹ isCH₃, R² is Cl, R³ is Cl, R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵ is Cl;the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ is Cl, R^(4a)is CH₃, R^(4b) is H, and R⁵ is Cl; the compound of Formula 1 wherein R¹is CH₃, R² is Cl, R³ is OCH₂CF₃, R^(4a) is CH(CH₃)₂, R^(4b) is H, and R⁵is Cl; the compound of Formula 1 wherein R¹ is CH₃, R² is Cl, R³ isOCH₂CF₃, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl; the compound ofFormula 1 wherein R¹ is Cl, R² is Cl, R³ is Br, R^(4a) is CH₃, R^(4b) isH, and R⁵ is Cl; and the compound of Formula 1 wherein R¹ is CH₃, R² isCl, R³ is OCH₂CF₃, R^(4a) is CH₃, R^(4b) is H, and R⁵ is Cl.
 9. Acomposition for controlling an invertebrate pest comprising abiologically effective amount of a compound of claim 1 and at least oneadditional component selected from the group consisting of surfactants,solid diluents and liquid diluents.
 10. A composition comprising abiologically effective amount of a compound of claim 1 and an effectiveamount of at least one additional biologically active compound or agent.11. A composition of claim 10 wherein at least one additionalbiologically active compound or agent is selected from arthropodicidesof the group consisting of pyrethroids, carbamates, neonicotinoids,neuronal sodium channel blockers, insecticidal macrocyclic lactones,γ-aminobutyric acid (GABA) antagonists, insecticidal ureas and juvenilehormone mimics.
 12. A composition of claim 10 wherein at least oneadditional biologically active compound or agent is selected frominsecticide, nematocide, acaricide or biological agents in the groupconsisting of abamectin, acephate, acetamiprid, amidoflumet, avermectin,azadirachtin, azinphos-methyl, bifenthrin, binfenazate, buprofezin,carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos,chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin,beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin,cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron,dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole,fenothicarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil,flonicamid, flucythrinate, tau-fluvalinate, flufenerim, flufenoxuron,fonophos, halofenozide, hexaflumuron, imidacloprid, indoxacarb,isofenphos, lufenuron, malathion, metaldehyde, methamidophos,methidathion, methomyl, methoprene, methoxychlor, monocrotophos,methoxyfenozide, nithiazin, novaluron, noviflumuron, oxamyl, parathion,parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon,pirimicarb, profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone,spinosad, spiromesifin, sulprofos, tebufenozide, teflubenzuron,tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam,thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon, triflumuron,aldicarb, oxamyl, fenamiphos, amitraz, chinomethionat, chlorobenzilate,cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide,fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; andbiological agents such as Bacillus thuringiensis including ssp. aizawaiand kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, andentomopathogenic bacteria, virus and fungi.
 13. A composition of claim10 wherein at least one additional biologically active compound or agentis selected from insecticide, nematocide, acaricide or biological agentsin the group consisting of cypermethrin, cyhalothrin, cyfluthrin andbeta-cyfluthrin, esfenvalerate, fenvalerate, tralomethrin, fenothicarb,methomyl, oxamyl, thiodicarb, clothianidin, imidacloprid, thiacloprid,indoxacarb, spinosad, abamectin, avermectin, emamectin, endosulfan,ethiprole, fipronil, flufenoxuron, triflumuron, diofenolan,pyriproxyfen, pymetrozine, amitraz, Bacillus thuringiensis, Bacillusthuringiensis delta endotoxin and entomophagous fungi.
 14. A method forcontrolling an invertebrate pest comprising contacting the invertebratepest or its environment with a biologically effective amount of acompound of claim
 1. 15. A method for controlling an invertebrate pestcomprising contacting the invertebrate pest or its environment with abiologically effective amount of a composition of claim
 10. 16. Acompound of Formula 2

wherein R¹ is CH₃, F, Cl or Br; R² is F, Cl, Br, I or CF₃; R³ is CF₃,Cl, Br or OCH₂CF₃; and R⁵ is Cl or Br.
 17. A compound of Formula 4

wherein R³ is CF₃, Cl, Br or OCH₂CF₃; and R⁵ is Cl or Br.
 18. The methodof claim 14 wherein a plant is contacted with a composition comprisingthe compound of Formula 1, the N-oxide thereof, or the agriculturallysuitable salt thereof, applied as a soil drench of a liquid formulation.19. The composition of claim 9 in the form of a soil drench liquidformulation.